Oxindole derivatives carrying an oxetane substituent and use thereof for treating vassopressin-related diseases

ABSTRACT

The present invention relates to novel substituted oxindole derivatives of formula (I), pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This claims priority to U.S. Patent Application No. 61/781,468, filed onMar. 14, 2013, and U.S. Patent Application No. 61/862,317, filed on Aug.5, 2013, the entire contents of all of which are fully incorporatedherein by reference.

The present invention relates to novel substituted oxindole derivatives,pharmaceutical compositions comprising them, and their use for thetreatment of vasopressin-related disorders.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible new therapeutic approaches for the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740; T. Ryckmans,Current Opinion in Drug Discovery & Development 13 (2010), 538-547; G.Decaux et al., Lancet 371 (2008), 1624-1632; R. Lemmens-Gruber, M.Kamyar, Cell. Mol. Life Sci. 63 (2006), 1766-1779).

1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously beendescribed as ligands of vasopressin receptors, for example in WO2005/030755, WO 2006/005609, WO 2006/080574, WO 2008/080970, WO2008/080971, WO 2008/080972, WO 2008/080973, WO 2009/071687, WO2009/071689, WO 2009/071690, WO2009/071691, WO 2009/083559, WO2010/009775 or WO 2010/142739.

Besides the binding affinity for the vasopressin V1b receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis ofvasopressin-related disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V1a receptor, i.e. the quotient of the binding affinity forthe V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means agreater V1b selectivity;2.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V2 receptor, i.e. the quotient of the binding affinity forthe V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greaterV1b selectivity;3.) a selectivity for the vasopressin V1b receptor compared with theoxytocin OT receptor, i.e. the quotient of the binding affinity for theOT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and thebinding affinity for the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1bselectivity.4.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);5.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;6.) a suitable solubility in water (in mg/ml);7.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in l·kg⁻¹), plasma clearance(in l·h⁻¹·kg⁻¹), AUC (area under the curve, area under theconcentration-time curve, in ng·h·l⁻¹), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);8.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187-199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compoundsfor the treatment or prophylaxis of various vasopressin-relateddiseases. The compounds were intended to have a high activity andselectivity, especially a high affinity and selectivity vis-à-vis thevasopressin V1b receptor. In addition, the substance of the inventionwas intended to have one or more of the aforementioned advantages 1.) to8.).

The object is achieved by compounds of the formula I

wherein

-   X¹ and X² are N or CH, with the proviso that X¹ and X² are not    simultaneously N;-   X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene or CO;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   R¹ and R², independently of each other, are selected from hydrogen,    halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,    C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R³ is selected from hydrogen, halogen, cyano, C₁-C₃-alkyl,    fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy,    fluorinated C₁-C₃-alkoxy and hydroxyl;-   R⁴ is selected from C₁-C₃-alkoxy;-   R⁵ is selected from hydrogen and C₁-C₃-alkoxy;-   R⁶ is selected from cyano and halogen;-   R⁷ is selected from hydrogen, halogen and cyano;-   R⁸ and R⁹, independently of each other and independently of each    occurrence, are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,    C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with the proviso that R⁸ and R⁹    are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are bound    to a carbon atom in α-position to a nitrogen ring atom; or-   two non-geminal radicals R⁸ form together a group —(CH₂)_(n)—, where    n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be    replaced a methyl group; or-   two non-geminal radicals R⁹ form together a group —(CH₂)_(n)—, where    n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be    replaced a methyl group;-   each R¹⁰ is independently selected from halogen, C₁-C₄-alkyl and    C₁-C₄-haloalkyl;-   a is 0, 1, 2, 3 or 4;-   b is 0, 1, 2, 3 or 4; and-   c is 0, 1, 2, 3 or 4;    and N-oxides, stereoisomers and the pharmaceutically acceptable    salts thereof, and the compound of the formula I, wherein at least    one of the atoms has been replaced by its stable, non-radioactive    isotope.

In a particular embodiment, the invention relates to compounds I,wherein

-   X¹ and X² are N or CH, with the proviso that X¹ and X² are not    simultaneously N;-   X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene or CO;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   R¹, R² and R³, independently of each other, are selected from    hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,    C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R⁴ is selected from C₁-C₃-alkoxy;-   R⁵ is selected from hydrogen and C₁-C₃-alkoxy;-   R⁶ is selected from cyano and halogen;-   R⁷ is selected from hydrogen, halogen and cyano;-   R⁸ and R⁹, independently of each other and independently of each    occurrence, are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,    C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with the proviso that R⁸ and R⁹    are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are bound    to a carbon atom in α-position to a nitrogen ring atom; or-   two non-geminal radicals R⁸ form together a group —(CH₂)_(n)—, where    n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be    replaced a methyl group; or-   two non-geminal radicals R⁹ form together a group —(CH₂)_(n)—, where    n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be    replaced a methyl group;-   each R¹⁰ is independently selected from halogen, C₁-C₄-alkyl and    C₁-C₄-haloalkyl;-   a is 0, 1, 2, 3 or 4;-   b is 0, 1, 2, 3 or 4; and-   c is 0, 1, 2, 3 or 4;    and N-oxides, stereoisomers and the pharmaceutically acceptable    salts thereof, and the compound of the formula I, wherein at least    one of the atoms has been replaced by its stable, non-radioactive    isotope.

Accordingly, the present invention relates to compounds of the formula I(also “compounds I” hereinafter) and the N-oxides, stereoisomers and thepharmaceutically acceptable salts of the compounds I of the compounds I.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a stereoisomer or a pharmaceuticallyacceptable salt thereof, or comprising at least one compound as definedabove or below wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope, preferably wherein at least onehydrogen atom has been replaced by a deuterium atom, in combination withat least one pharmaceutically acceptable carrier and/or auxiliarysubstance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof for the treatment and/or prophylaxis of vasopressin-relateddiseases, especially of disorders which respond to the modulation of thevasopressin receptor, in particular of the V1b receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of vasopressin-related diseases; especiallyof disorders which respond to the modulation of the vasopressinreceptor, in particular of the V1b receptor.

The pharmaceutically acceptable salts of compounds of the formula I,which are also referred to as physiologically tolerated salts, areordinarily obtainable by reacting the free base of the compounds I ofthe invention (i.e. of the compounds I according to structural formulaI) with suitable acids. Examples of suitable acids are listed in“Fortschritte der Arzneimittelforschung”, 1966, Birkhäuser Verlag, vol.10, pp. 224-285. These include for example hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, trifluoroacetic acid, formic acid, maleic acid and fumaricacid.

Halogen in the terms of the present invention is fluorine, chlorine,bromine or iodine, preferably fluorine, chlorine or bromine andespecially fluorine or chlorine.

C₁-C₃-Alkyl is a linear or branched alkyl radical having 1 to 3 carbonatoms, such as methyl, ethyl, n-propyl or isopropyl. C₁-C₄-Alkyl is alinear or branched alkyl radical having 1 to 4 carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl ortert-butyl.

C₁-C₄-Haloalkyl is C₁-C₄-alkyl as defined above wherein at least one,e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogenatom. Preferably, C₁-C₄-haloalkyl is fluorinated C₁-C₄-alkyl. This is astraight-chain or branched alkyl group having from 1 to 4, in particular1 to 3 carbon atoms (=fluorinated C₁-C₃-alkyl), more preferably 1 or 2carbon atoms (=fluorinated C₁-C₂-alkyl), wherein at least one, e.g. 1,2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms,such as in fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,(R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl,(R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl,1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl,3,3,3-trifluoropropyl, 2-fluoropropyl, 2-fluoro-1-methylethyl,(R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl,2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl,(S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl,(R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl,2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl,(S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl,1-(difluoromethyl)-2,2-difluoroethyl, 1-fluorobutyl, (R)-1-fluorobutyl,(S)-1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl,1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl, etc.

C₁-C₄-Hydroxyalkyl is C₁-C₄-alkyl as defined above wherein one of thehydrogen atoms is replaced by a hydroxyl group. Examples arehydroxymethyl, 1- and 2-hydroxyethyl, 1-, 2- and 3-hydroxy-n-propyl,1-(hydroxymethyl)-ethyl and the like.

C₁-C₃-Alkoxy is a linear or branched alkyl radical linked via an oxygenatom and having 1 to 3 carbon atoms. Examples are methoxy, ethoxy,n-propoxy and isopropoxy. C₁-C₄-Alkoxy is a linear or branched alkylradical linked via an oxygen atom and having 1 to 4 carbon atoms.Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, isobutoxy and tert-butoxy.

C₁-C₄-Haloalkoxy is C₁-C₄-alkoxy as defined above wherein at least one,e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogenatom. Preferably, C₁-C₄-haloalkoxy is fluorinated C₁-C₄-alkoxy. This isa straight-chain or branched alkoxy group having from 1 to 4, inparticular 1 to 3 carbon atoms (=fluorinated C₁-C₃-alkoxy), morepreferably 1 or 2 carbon atoms (=fluorinated C₁-C₂-alkoxy), wherein atleast one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced byfluorine atoms, such as in fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-fluoroethoxy, (R)-1-fluoroethoxy,(S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoropropoxy,(R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy,3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy,3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, 2-fluoro-1-methylethoxy,(R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy,2,2-difluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy,(S)-2,2-difluoro-1-methylethoxy, 1,2-difluoro-1-methylethoxy,(R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy,2,2,2-trifluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy,(S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy,1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorobutoxy,(S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy,1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy,4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, etc

C₁-C₄-Alkylene is a divalent bridging group, such as CH₂, CH₂CH₂,CH(CH₃), (CH₂)₃, CH(CH₃)CH₂, CH₂CH(CH₃), C(CH₃)₂, (CH₂)₄, CH(CH₃)CH₂CH₂,C(CH₃)₂CH₂, CH₂CH(CH₃)CH₂, CH₂C(CH₃)₂, CH₂CH₂CH(CH₃), CH₂C(CH₃)₂ and thelike.

C₁-C₄-Haloalkylene is a divalent C₁-C₄-alkylene bridging group asdefined above, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by a halogen atom. Preferably,C₁-C₄-haloalkylene is fluorinated C₁-C₄-alkylene. Examples are CHF, CF₂,CHFCH₂, CF₂CH₂, CH₂CHF, CH₂CF₂CF₂CF₂, CF(CH₃), CH(CF₃), CF(CF₃),CHFCH₂CH₂, CH₂CHFCH₂, CH₂CF₂CH₂, CH₂CH(CF₃)CH₂ and the like.

The compounds of the invention of the formula I and their N-oxides,stereoisomers and pharmacologically acceptable salts may also be presentin the form of solvates or hydrates. Solvates mean in the context of thepresent invention crystalline forms of the compounds I or of theirpharmaceutically acceptable salts which comprise solvent moleculesincorporated in the crystal lattice. The solvent molecules arepreferably incorporated in stoichiometric ratios. Hydrates are aspecific form of solvates; the solvent in this case being water.

The statements made hereinafter concerning suitable and preferredfeatures of the invention, especially concerning the radicals R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X¹, X², X³, X⁴, X⁵, a, b, c, and n inthe compound I, but also concerning the features of the process of theinvention and of the use according to the invention apply both taken ontheir own as well as preferably in any possible combination with oneanother.

The compounds I are preferably provided in the form of the free base(i.e. according to structural formula I) or in the form of their acidaddition salts.

In a preferred embodiment, R¹, R² and R³, independently of each other,are selected from hydrogen, fluorine, cyano, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxyand trifluoromethoxy. More preferably, R¹, R² and R³, independently ofeach other, are selected from hydrogen, fluorine, cyano, methyl andmethoxy.

Preferably, R¹ is selected from hydrogen, fluorine, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy and trifluoromethoxy. More preferably, R¹ is selectedfrom hydrogen, fluorine, methyl and methoxy.

Preferably, R² is selected from hydrogen, fluorine, cyano, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy and trifluoromethoxy. More preferably, R² is selectedfrom hydrogen, fluorine, cyano, methyl, methoxy, fluoromethoxy,difluoromethoxy and trifluoromethoxy; especially from hydrogen,fluorine, cyano, methoxy, fluoromethoxy, difluoromethoxy andtrifluoromethoxy. In particular, R² is selected from hydrogen, cyano,methyl, methoxy and fluorine; more especially from hydrogen, cyano,methoxy and fluorine.

Preferably, R³ is selected from hydrogen, fluorine, methyl,fluoromethyl, difluoromethyl, trifluoromethyl and hydroxyl, and morepreferably from hydrogen, fluorine, methyl, fluoromethyl, difluoromethyland trifluoromethyl. In particular, R³ is selected from hydrogen,fluorine and methyl.

R³ is preferably bound in 3- or 5-position, relative to the 2- and4-positions of R¹ and R².

Preferably, R⁴ is selected from methoxy and ethoxy, and is in particularmethoxy, especially in case that X⁴ is N. In an alternative preferredembodiment, R⁴ is isopropoxy.

Preferably, R⁵ is hydrogen or methoxy, and in particular hydrogen.

Preferably, R⁶ is selected from cyano, fluorine and chlorine.

Preferably, R⁷ is selected from hydrogen and fluorine.

Preferably, each R⁸ is independently selected from halogen andC₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁸ isnot halogen if it is bound to a carbon atom in α-position to a nitrogenring atom, or two non-geminal radicals R⁸ form together a group —CH₂— or—CH₂CH₂—, preferably —CH₂—. More preferably, two non-geminal radicals R⁸form together a group —CH₂—. The two non-geminal radicals R⁸ formingtogether a group —CH₂— are preferably bound in 2- and 5-positions,relative to the 4-position of X¹.

Preferably, each R⁹ is independently selected from halogen andC₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁸ isnot halogen if it is bound to a carbon atom in α-position to a nitrogenring atom, or two non-geminal radicals R⁹ form together a group —CH₂— or—CH₂CH₂—, preferably —CH₂—. More preferably, two non-geminal radicals R⁹form together a group —CH₂—. The two non-geminal radicals R⁹ formingtogether a group —CH₂— are preferably bound in 2- and 5-positions,relative to the 1-position of X².

Preferably, each R¹⁰ is independently selected from halogen andC₁-C₄-alkyl, preferably from F, Cl and CH₃, and is in particular CH₃.

In one embodiment, X¹ is N and X² is CH.

In another embodiment, X¹ is CH and X² is N.

In another embodiment, X¹ is CH and X² is CH.

Preferably, X³ is a bond or CH₂. Specifically, X³ is a bond.

X⁴ is N or CH. Specifically, X⁴ is N.

X⁵ is C—R¹ or N. Specifically, X⁵ is C—R¹.

Preferably, a is 0, 1 or 2, in particular 0 or 2.

Preferably, b is 0, 1 or 2, in particular 0 or 2.

Preferably, c is 0, 1 or 2, more preferably 0 or 1, in particular 0.

The invention preferably relates to compounds of the formula I in which

-   R¹, R² and R³, independently of each other, are selected from    hydrogen, fluorine, cyano, methyl and methoxy;-   R⁴ is selected from methoxy, ethoxy and isopropoxy; in particular    methoxy and ethoxy;-   R⁵ is hydrogen or methoxy;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   each R⁸ is independently selected from halogen and C₁-C₄-alkyl or    two non-geminal radicals R⁸ form together a group —CH₂— or —CH₂CH₂—;-   each R⁹ is independently selected from halogen and C₁-C₄-alkyl or    two non-geminal radicals R⁹ form together a group —CH₂— or —CH₂CH₂—;-   each R¹⁰ is independently selected from halogen and C₁-C₄-alkyl;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   a is 0, 1 or 2;-   b is 0, 1 or 2;-   c is 0, 1 or 2;    and the pharmaceutically acceptable salts thereof.

The invention more preferably relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano, methyl, methoxy and fluorine;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy, ethoxy and isopropoxy;-   R⁵ is hydrogen or methoxy;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   each R⁸ is independently selected from F, Cl and methyl, or two    non-geminal radicals R⁸ form together a group —CH₂—;-   each R⁹ is independently selected from F, Cl and methyl, or two    non-geminal radicals R⁹ form together a group —CH₂—;-   each R¹⁰ is independently selected from F, Cl and methyl;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   a is 0, 1 or 2, preferably 0 or 2;-   b is 0, 1 or 2, preferably 0 or 2;-   c is 0, 1 or 2, preferably 0 or 1;    and the pharmaceutically acceptable salts thereof.-   The invention more preferably relates to compounds of the formula I    in which-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano, methoxy and fluorine;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy;-   R⁵ is hydrogen or methoxy;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   each R⁸ is independently selected from F, Cl and methyl or two    non-geminal radicals R⁸ form together a group —CH₂—;-   each R⁹ is independently selected from F, Cl and methyl or two    non-geminal radicals R⁹ form together a group —CH₂—;-   each R¹⁰ is independently selected from F, Cl and methyl;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   a is 0, 1 or 2, preferably 0 or 2;-   b is 0, 1 or 2, preferably 0 or 2;-   c is 0, 1 or 2, preferably 0;    and the pharmaceutically acceptable salts thereof.

The invention more preferably relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano and methoxy;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy;-   R⁵ is hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   each R⁸ is independently selected from F, Cl and methyl or two    non-geminal radicals R⁸ form together a group —CH₂—;-   each R⁹ is independently selected from F, Cl and methyl or two    non-geminal radicals R⁹ form together a group —CH₂—;-   each R¹⁰ is independently selected from F, Cl and methyl;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   a is 0, 1 or 2, preferably 0;-   b is 0, 1 or 2, preferably 0 or 2;-   c is 0, 1 or 2, preferably 0;    and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano, methyl, methoxy and fluorine;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy, ethoxy and isopropoxy, in particular    from methoxy and ethoxy, and is specifically methoxy;-   R⁵ is hydrogen or methoxy, in particular hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   two non-geminal radicals R⁸ form together a group —CH₂—;-   two non-geminal radicals R⁹ form together a group —CH₂—;-   R¹⁰ is methyl;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N or CH;-   X⁵ is C—R¹ or N;-   a is 0 or 2;-   b is 0 or 2;-   c is 0 or 1;    and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano and methoxy;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy, in particular from methoxy;-   R⁵ is hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   two non-geminal radicals R⁸ form together a group —CH₂—;-   two non-geminal radicals R⁹ form together a group —CH₂—;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N;-   X⁵ is C—R¹;-   a is 0 or 2;-   b is 0 or 2;-   c is 0;    and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano and methoxy;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy;-   R⁵ is hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   two non-geminal radicals R⁸ form together a group —CH₂—;-   two non-geminal radicals R⁹ form together a group —CH₂—;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is CH;-   X⁵ is C—R¹;-   a is 0 or 2;-   b is 0 or 2;-   c is 0;    and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano and methoxy;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy, in particular from methoxy;-   R⁵ is hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   two non-geminal radicals R⁸ form together a group —CH₂—;-   two non-geminal radicals R⁹ form together a group —CH₂—;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is N;-   X⁵ is N;-   a is 0 or 2;-   b is 0 or 2;-   c is 0;    and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy;-   R² is selected from hydrogen, cyano and methoxy;-   R³ is selected from hydrogen, fluorine and methyl;-   R⁴ is selected from methoxy and ethoxy;-   R⁵ is hydrogen;-   R⁶ is selected from cyano, fluorine and chlorine;-   R⁷ is hydrogen or fluorine;-   two non-geminal radicals R⁸ form together a group —CH₂—;-   two non-geminal radicals R⁹ form together a group —CH₂—;-   X¹ is N or CH;-   X² is N or CH;-   where X¹ and X² are not simultaneously N;-   X³ is a bond or CH₂;-   X⁴ is CH;-   X⁵ is N;-   a is 0 or 2;-   b is 0 or 2;-   c is 0;    and the pharmaceutically acceptable salts thereof.

Examples of preferred embodiment of the present invention are compoundsof the formulae I.1 to I.84 and the N-oxides, stereoisomers and thepharmaceutically acceptable salts thereof, in which the radicals R¹, R²,R³, R⁶ and R⁷ have one of the above general or preferred meanings,R^(8a), R^(8b), R^(8c) and R^(8d) are hydrogen or have one of thegeneral or preferred meanings given above for R⁸, R^(9a), R^(9b), R^(9c)and R^(9d) are hydrogen or have one of the general or preferred meaningsgiven above for R⁹, and R^(10a), R^(10b), R^(10c) and R^(10d) arehydrogen or have one of the general or preferred meanings given abovefor R¹⁰. In particular, preferred compounds are the individual compoundscompiled in the tables 1 to 2520 below. Moreover, the meanings mentionedbelow for the individual variables in the tables are per se,independently of the combination in which they are mentioned, aparticularly preferred embodiment of the substituents in question.

Table 1

Compounds of the formula I.1 in which R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d)are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds ineach case to one row of Table A

Table 2

Compounds of the formula I.1 in which R^(8a) is methyl R^(8b), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 3

Compounds of the formula I.1 in which R^(8b) is methyl, R^(8a), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 4

Compounds of the formula I.1 in which R^(8a) and R^(8b) are methyl,R^(8e), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 5

Compounds of the formula I.1 in which R^(8a) and R^(8c) are methyl,R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 6

Compounds of the formula I.1 in which R^(8a) and R^(8d) are methyl,R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 7

Compounds of the formula I.1 in which R^(8a) and R^(8c) form together agroup —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 8

Compounds of the formula I.1 in which R^(9a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 9

Compounds of the formula I.1 in which R^(9b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 10

Compounds of the formula I.1 in which R^(9a) and R^(9b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 11

Compounds of the formula I.1 in which R^(9a) and R^(9c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 12

Compounds of the formula I.1 in which R^(9a) and R^(9d) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 13

Compounds of the formula I.1 in which R^(9a) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 14

Compounds of the formula I.1 in which R^(9a) and R^(9d) are fluorine,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 15

Compounds of the formula I.1 in which R^(9a) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 16

Compounds of the formula I.1 in which R^(9a) and R^(9d) are chlorine,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 17

Compounds of the formula I.1 in which R^(9a) and R^(9c) form together agroup —CH₂—, R^(8a), R^(8b), R^(8C), R^(8d), R^(9b), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 18

Compounds of the formula I.1 in which R^(8a) and R^(9a) are methylR^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 19

Compounds of the formula I.1 in which R^(8b) and R^(9b) are methylR^(8a), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 20

Compounds of the formula I.1 in which R^(10a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 21

Compounds of the formula I.1 in which R^(10b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 22

Compounds of the formula I.1 in which R^(10a) and R^(10b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 23

Compounds of the formula I.1 in which R^(10b) and R^(10c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 24

Compounds of the formula I.1 in which R^(10a), R^(10b) and R^(10c) aremethyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 25

Compounds of the formula I.1 in which R^(10a), R^(10b) and R^(10d) aremethyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d)and R^(10c) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 26

Compounds of the formula I.1 in which R^(8a), R^(9a) and R^(10a) aremethyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 27

Compounds of the formula I.1 in which R^(10a) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 28

Compounds of the formula I.1 in which R^(10b) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 29

Compounds of the formula I.1 in which R^(10a) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 30

Compounds of the formula I.1 in which R^(10b) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 31

Compounds of the formula I.2 in which R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d)are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds ineach case to one row of Table A

Table 32

Compounds of the formula I.2 in which R^(8a) is methyl, R^(8b), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 33

Compounds of the formula I.2 in which R^(8b) is methyl, R^(8a), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 34

Compounds of the formula I.2 in which R^(8a) and R^(8b) are methyl,R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 35

Compounds of the formula I.2 in which R^(8a) and R^(8c) are methyl,R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 36

Compounds of the formula I.2 in which R^(8a) and R^(8d) are methyl,R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 37

Compounds of the formula I.2 in which R^(8b) is fluorine, R^(8a),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 38

Compounds of the formula I.2 in which R^(8b) and R^(8c) are fluorine,R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 39

Compounds of the formula I.2 in which R^(8b) is chlorine, R^(8a),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 40

Compounds of the formula I.2 in which R^(8b) and R^(8c) are chlorine,R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 41

Compounds of the formula I.2 in which R^(8a) and R^(8c) form together agroup —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 42

Compounds of the formula I.2 in which R^(9a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 43

Compounds of the formula I.2 in which R^(9b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 44

Compounds of the formula I.2 in which R^(9a) and R^(9b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 45

Compounds of the formula I.2 in which R^(9a) and R^(9c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 46

Compounds of the formula I.2 in which R^(9a) and R^(9d) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 47

Compounds of the formula I.2 in which R^(9a) and R^(9c) form together agroup —CH₂—, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 48

Compounds of the formula I.2 in which R^(8a) and R^(9a) are methylR^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 49

Compounds of the formula I.2 in which R^(8b) and R^(9b) are methylR^(8a), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 50

Compounds of the formula I.2 in which R^(10a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 51

Compounds of the formula I.2 in which R^(10b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 52

Compounds of the formula I.2 in which R^(10a) and R^(10b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 53

Compounds of the formula I.2 in which R^(10b) and R^(10c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 54

Compounds of the formula I.2 in which R^(10a), R^(10b) and R^(10c) aremethyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 55

Compounds of the formula I.2 in which R^(10a), R^(10b) and R^(10d) aremethyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d)and R^(10c) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 56

Compounds of the formula I.2 in which R^(8a), R^(9a) and R^(10a) aremethyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 57

Compounds of the formula I.2 in which R^(10a) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 58

Compounds of the formula I.2 in which R^(10b) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 59

Compounds of the formula I.2 in which R^(10a) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 60

Compounds of the formula I.2 in which R^(10b) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 61

Compounds of the formula I.3 in which R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d)are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds ineach case to one row of Table A

Table 62

Compounds of the formula I.3 in which R^(8a) is methyl, R^(8b), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 63

Compounds of the formula I.3 in which R^(8b) is methyl, R^(8a), R^(8c),R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 64

Compounds of the formula I.3 in which R^(8a) and R^(8b) are methyl,R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 65

Compounds of the formula I.3 in which R^(8a) and R^(8b) are methyl,R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 66

Compounds of the formula I.3 in which R^(8a) and R^(8d) are methyl,R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 67

Compounds of the formula I.3 in which R^(8b) is fluorine, R^(8a),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 68

Compounds of the formula I.3 in which R^(8b) and R^(8c) are fluorine,R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 69

Compounds of the formula I.3 in which R^(8b) is chlorine, R^(8a),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 70

Compounds of the formula I.3 in which R^(8b) and R^(8c) are chlorine,R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 71

Compounds of the formula I.3 in which R^(8a) and R^(8c) form together agroup —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 72

Compounds of the formula I.3 in which R^(9a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 73

Compounds of the formula I.3 in which R^(9b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 74

Compounds of the formula I.3 in which R^(9a) and R^(9b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 75

Compounds of the formula I.3 in which R^(9a) and R^(9c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 76

Compounds of the formula I.3 in which R^(9a) and R^(9d) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 77

Compounds of the formula I.3 in which R^(9a) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 78

Compounds of the formula I.3 in which R^(9a) and R^(9d) are fluorine,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 79

Compounds of the formula I.3 in which R^(9a) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 80

Compounds of the formula I.3 in which R^(9a) and R^(9d) are chlorine,R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b),R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for acompound corresponds in each case to one row of Table A

Table 81

Compounds of the formula I.3 in which R^(9a) and R^(9c) form together agroup —CH₂—, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ fora compound corresponds in each case to one row of Table A

Table 82

Compounds of the formula I.3 in which R^(10a) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 83

Compounds of the formula I.3 in which R^(10b) is methyl, R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) andR^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 84

Compounds of the formula I.3 in which R^(10a) and R^(10b) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 85

Compounds of the formula I.3 in which R^(10b) and R^(10c) are methyl,R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 86

Compounds of the formula I.3 in which R^(10a), R^(10b) and R^(10c) aremethyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 87

Compounds of the formula I.3 in which R^(10a) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 88

Compounds of the formula I.3 in which R^(10b) is fluorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 89

Compounds of the formula I.3 in which R^(10a) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Table 90

Compounds of the formula I.3 in which R^(10b) is chlorine, R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c)and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compoundcorresponds in each case to one row of Table A

Tables 91 to 120

Compounds of the formula I.4 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 121 to 150

Compounds of the formula I.5 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 151 to 180

Compounds of the formula I.6 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 181 to 210

Compounds of the formula I.7 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 211 to 240

Compounds of the formula I.8 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 241 to 270

Compounds of the formula I.9 in which the combination of R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b),R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R²,R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable A

Tables 271 to 300

Compounds of the formula I.10 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 301 to 330

Compounds of the formula I.11 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 331 to 360

Compounds of the formula I.12 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 361 to 390

Compounds of the formula I.13 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 391 to 420

Compounds of the formula I.14 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 421 to 450

Compounds of the formula I.15 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 451 to 480

Compounds of the formula I.16 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 481 to 510

Compounds of the formula I.17 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 511 to 540

Compounds of the formula I.18 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 541 to 570

Compounds of the formula I.19 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 571 to 600

Compounds of the formula I.20 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 601 to 630

Compounds of the formula I.21 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 631 to 660

Compounds of the formula I.22 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 661 to 690

Compounds of the formula I.23 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 691 to 720

Compounds of the formula I.24 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 721 to 750

Compounds of the formula I.25 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 751 to 780

Compounds of the formula I.26 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 781 to 810

Compounds of the formula I.27 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 811 to 840

Compounds of the formula I.28 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 841 to 870

Compounds of the formula I.29 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 871 to 900

Compounds of the formula I.30 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 901 to 930

Compounds of the formula I.31 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 931 to 960

Compounds of the formula I.32 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 961 to 990

Compounds of the formula I.33 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 991 to 1020

Compounds of the formula I.34 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 1021 to 1050

Compounds of the formula I.35 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1051 to 1080

Compounds of the formula I.36 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1081 to 1110

Compounds of the formula I.37 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1111 to 1140

Compounds of the formula I.38 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1141 to 1170

Compounds of the formula I.39 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1171 to 1200

Compounds of the formula I.40 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1201 to 1230

Compounds of the formula I.41 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1231 to 1260

Compounds of the formula I.42 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1261 to 1290

Compounds of the formula I.43 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1291 to 1320

Compounds of the formula I.44 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1321 to 1350

Compounds of the formula I.45 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1351 to 1380

Compounds of the formula I.46 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1381 to 1410

Compounds of the formula I.47 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1411 to 1440

Compounds of the formula I.48 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1441 to 1470

Compounds of the formula I.49 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1471 to 1500

Compounds of the formula I.50 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1501 to 1530

Compounds of the formula I.51 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1531 to 1560

Compounds of the formula I.52 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 1561 to 1590

Compounds of the formula I.53 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1591 to 1620

Compounds of the formula I.54 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 1621 to 1650

Compounds of the formula I.55 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 1651 to 1680

Compounds of the formula I.56 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1681 to 1710

Compounds of the formula I.57 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1711 to 1740

Compounds of the formula I.58 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 1741 to 1770

Compounds of the formula I.59 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1771 to 1800

Compounds of the formula I.60 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1801 to 1830

Compounds of the formula I.61 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 1831 to 1860

Compounds of the formula I.62 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1861 to 1890

Compounds of the formula I.63 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1891 to 1920

Compounds of the formula I.64 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 1921 to 1950

Compounds of the formula I.65 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1951 to 1980

Compounds of the formula I.66 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 1981 to 2010

Compounds of the formula I.67 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 2011 to 2040

Compounds of the formula I.68 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2041 to 2070

Compounds of the formula I.69 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2071 to 2100

Compounds of the formula I.70 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 2101 to 2130

Compounds of the formula I.71 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2131 to 2160

Compounds of the formula I.72 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2161 to 2190

Compounds of the formula I.73 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 2191 to 2220

Compounds of the formula I.74 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 2221 to 2250

Compounds of the formula I.75 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 2251 to 2280

Compounds of the formula I.76 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 2281 to 2310

Compounds of the formula I.77 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2311 to 2340

Compounds of the formula I.78 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2341 to 2370

Compounds of the formula I.79 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table A

Tables 2370 to 2400

Compounds of the formula I.80 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 2401 to 2430

Compounds of the formula I.81 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to onerow of Table A

Tables 2431 to 2460

Compounds of the formula I.82 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, andR², R³, R⁶ and R⁷ for a compound corresponds in each case to one row ofTable B

Tables 2461 to 2490

Compounds of the formula I.83 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

Tables 2491 to 2520

Compounds of the formula I.84 in which the combination of R^(8a),R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a),R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90,and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one rowof Table B

TABLE A Example No. R¹ R² R³ R⁶ R⁷ A-1. H H H CN H A-2. F H H CN H A-3.CH₃ H H CN H A-4. OCH₃ H H CN H A-5. CH₂F H H CN H A-6. CHF₂ H H CN HA-7. CF₃ H H CN H A-8. OCH₂F H H CN H A-9. OCHF₂ H H CN H A-10. OCF₃ H HCN H A-11. H F H CN H A-12. H CH₃ H CN H A-13. H OCH₃ H CN H A-14. H CNH CN H A-15. H CH₂F H CN H A-16. H CHF₂ H CN H A-17. H CF₃ H CN H A-18.H OCH₂F H CN H A-19. H OCHF₂ H CN H A-20. H OCF₃ H CN H A-21. H H 3-F CNH A-22. H H 3-CH₃ CN H A-23. H H 3-OCH₃ CN H A-24. H H 5-F CN H A-25. HH 5-CH₃ CN H A-26. H H 5-OCH₃ CN H A-27. F F H CN H A-28. F CH₃ H CN HA-29. F OCH₃ H CN H A-30. F CN H CN H A-31. F CH₂F H CN H A-32. F CHF₂ HCN H A-33. F CF₃ H CN H A-34. F OCH₂F H CN H A-35. F OCHF₂ H CN H A-36.F OCF₃ H CN H A-37. F H 3-F CN H A-38. F H 3-CH₃ CN H A-39. F H 3-OCH₃CN H A-40. F H 5-F CN H A-41. F H 5-CH₃ CN H A-42. F H 5-OCH₃ CN H A-43.CH₃ F H CN H A-44. CH₃ CH₃ H CN H A-45. CH₃ OCH₃ H CN H A-46. CH₃ CN HCN H A-47. CH₃ CH₂F H CN H A-48. CH₃ CHF₂ H CN H A-49. CH₃ CF₃ H CN HA-50. CH₃ OCH₂F H CN H A-51. CH₃ OCHF₂ H CN H A-52. CH₃ OCF₃ H CN HA-53. CH₃ H 3-F CN H A-54. CH₃ H 3-CH₃ CN H A-55. CH₃ H 3-OCH₃ CN HA-56. CH₃ H 5-F CN H A-57. CH₃ H 5-CH₃ CN H A-58. CH₃ H 5-OCH₃ CN HA-59. OCH₃ F H CN H A-60. OCH₃ CH₃ H CN H A-61. OCH₃ OCH₃ H CN H A-62.OCH₃ CN H CN H A-63. OCH₃ CH₂F H CN H A-64. OCH₃ CHF₂ H CN H A-65. OCH₃CF₃ H CN H A-66. OCH₃ OCH₂F H CN H A-67. OCH₃ OCHF₂ H CN H A-68. OCH₃OCF₃ H CN H A-69. OCH₃ H 3-F CN H A-70. OCH₃ H 3-CH₃ CN H A-71. OCH₃ H3-OCH₃ CN H A-72. OCH₃ H 5-F CN H A-73. OCH₃ H 5-CH₃ CN H A-74. OCH₃ H5-OCH₃ CN H A-75. H F 3-F CN H A-76. H F 3-CH₃ CN H A-77. H F 3-OCH₃ CNH A-78. H F 5-F CN H A-79. H F 5-CH₃ CN H A-80. H F 5-OCH₃ CN H A-81. HCH₃ 3-F CN H A-82. H CH₃ 3-CH₃ CN H A-83. H CH₃ 3-OCH₃ CN H A-84. H CH₃5-F CN H A-85. H CH₃ 5-CH₃ CN H A-86. H CH₃ 5-OCH₃ CN H A-87. H OCH₃ 3-FCN H A-88. H OCH₃ 3-CH₃ CN H A-89. H OCH₃ 3-OCH₃ CN H A-90. H OCH₃ 5-FCN H A-91. H OCH₃ 5-CH₃ CN H A-92. H OCH₃ 5-OCH₃ CN H A-93. H CN 3-F CNH A-94. H CN 3-CH₃ CN H A-95. H CN 3-OCH₃ CN H A-96. H CN 5-F CN H A-97.H CN 5-CH₃ CN H A-98. H CN 5-OCH₃ CN H A-99. H CH₂F 3-F CN H A-100. HCH₂F 3-CH₃ CN H A-101. H CH₂F 3-OCH₃ CN H A-102. H CH₂F 5-F CN H A-103.H CH₂F 5-CH₃ CN H A-104. H CH₂F 5-OCH₃ CN H A-105. H CHF₂ 3-F CN HA-106. H CHF₂ 3-CH₃ CN H A-107. H CHF₂ 3-OCH₃ CN H A-108. H CHF₂ 5-F CNH A-109. H CHF₂ 5-CH₃ CN H A-110. H CHF₂ 5-OCH₃ CN H A-111. H CF₃ 3-F CNH A-112. H CF₃ 3-CH₃ CN H A-113. H CF₃ 3-OCH₃ CN H A-114. H CF₃ 5-F CN HA-115. H CF₃ 5-CH₃ CN H A-116. H CF₃ 5-OCH₃ CN H A-117. H OCH₂F 3-F CN HA-118. H OCH₂F 3-CH₃ CN H A-119. H OCH₂F 3-OCH₃ CN H A-120. H OCH₂F 5-FCN H A-121. H OCH₂F 5-CH₃ CN H A-122. H OCH₂F 5-OCH₃ CN H A-123. H OCHF₂3-F CN H A-124. H OCHF₂ 3-CH₃ CN H A-125. H OCHF₂ 3-OCH₃ CN H A-126. HOCHF₂ 5-F CN H A-127. H OCHF₂ 5-CH₃ CN H A-128. H OCHF₂ 5-OCH₃ CN HA-129. H OCF₃ 3-F CN H A-130. H OCF₃ 3-CH₃ CN H A-131. H OCF₃ 3-OCH₃ CNH A-132. H OCF₃ 5-F CN H A-133. H OCF₃ 5-CH₃ CN H A-134. H OCF₃ 5-OCH₃CN H A-135. F F 3-F CN H A-136. F F 3-CH₃ CN H A-137. F F 3-OCH₃ CN HA-138. F F 5-F CN H A-139. F F 5-CH₃ CN H A-140. F F 5-OCH₃ CN H A-141.F CH₃ 3-F CN H A-142. F CH₃ 3-CH₃ CN H A-143. F CH₃ 3-OCH₃ CN H A-144. FCH₃ 5-F CN H A-145. F CH₃ 5-CH₃ CN H A-146. F CH₃ 5-OCH₃ CN H A-147. FOCH₃ 3-F CN H A-148. F OCH₃ 3-CH₃ CN H A-149. F OCH₃ 3-OCH₃ CN H A-150.F OCH₃ 5-F CN H A-151. F OCH₃ 5-CH₃ CN H A-152. F OCH₃ 5-OCH₃ CN HA-153. F CN 3-F CN H A-154. F CN 3-CH₃ CN H A-155. F CN 3-OCH₃ CN HA-156. F CN 5-F CN H A-157. F CN 5-CH₃ CN H A-158. F CN 5-OCH₃ CN HA-159. F CH₂F 3-F CN H A-160. F CH₂F 3-CH₃ CN H A-161. F CH₂F 3-OCH₃ CNH A-162. F CH₂F 5-F CN H A-163. F CH₂F 5-CH₃ CN H A-164. F CH₂F 5-OCH₃CN H A-165. F CHF₂ 3-F CN H A-166. F CHF₂ 3-CH₃ CN H A-167. F CHF₂3-OCH₃ CN H A-168. F CHF₂ 5-F CN H A-169. F CHF₂ 5-CH₃ CN H A-170. FCHF₂ 5-OCH₃ CN H A-171. F CF₃ 3-F CN H A-172. F CF₃ 3-CH₃ CN H A-173. FCF₃ 3-OCH₃ CN H A-174. F CF₃ 5-F CN H A-175. F CF₃ 5-CH₃ CN H A-176. FCF₃ 5-OCH₃ CN H A-177. F OCH₂F 3-F CN H A-178. F OCH₂F 3-CH₃ CN H A-179.F OCH₂F 3-OCH₃ CN H A-180. F OCH₂F 5-F CN H A-181. F OCH₂F 5-CH₃ CN HA-182. F OCH₂F 5-OCH₃ CN H A-183. F OCHF₂ 3-F CN H A-184. F OCHF₂ 3-CH₃CN H A-185. F OCHF₂ 3-OCH₃ CN H A-186. F OCHF₂ 5-F CN H A-187. F OCHF₂5-CH₃ CN H A-188. F OCHF₂ 5-OCH₃ CN H A-189. F OCF₃ 3-F CN H A-190. FOCF₃ 3-CH₃ CN H A-191. F OCF₃ 3-OCH₃ CN H A-192. F OCF₃ 5-F CN H A-193.F OCF₃ 5-CH₃ CN H A-194. F OCF₃ 5-OCH₃ CN H A-195. CH₃ F 3-F CN H A-196.CH₃ F 3-CH₃ CN H A-197. CH₃ F 3-OCH₃ CN H A-198. CH₃ F 5-F CN H A-199.CH₃ F 5-CH₃ CN H A-200. CH₃ F 5-OCH₃ CN H A-201. CH₃ CH₃ 3-F CN H A-202.CH₃ CH₃ 3-CH₃ CN H A-203. CH₃ CH₃ 3-OCH₃ CN H A-204. CH₃ CH₃ 5-F CN HA-205. CH₃ CH₃ 5-CH₃ CN H A-206. CH₃ CH₃ 5-OCH₃ CN H A-207. CH₃ OCH₃ 3-FCN H A-208. CH₃ OCH₃ 3-CH₃ CN H A-209. CH₃ OCH₃ 3-OCH₃ CN H A-210. CH₃OCH₃ 5-F CN H A-211. CH₃ OCH₃ 5-CH₃ CN H A-212. CH₃ OCH₃ 5-OCH₃ CN HA-213. CH₃ CN 3-F CN H A-214. CH₃ CN 3-CH₃ CN H A-215. CH₃ CN 3-OCH₃ CNH A-216. CH₃ CN 5-F CN H A-217. CH₃ CN 5-CH₃ CN H A-218. CH₃ CN 5-OCH₃CN H A-219. CH₃ CH₂F 3-F CN H A-220. CH₃ CH₂F 3-CH₃ CN H A-221. CH₃ CH₂F3-OCH₃ CN H A-222. CH₃ CH₂F 5-F CN H A-223. CH₃ CH₂F 5-CH₃ CN H A-224.CH₃ CH₂F 5-OCH₃ CN H A-225. CH₃ CHF₂ 3-F CN H A-226. CH₃ CHF₂ 3-CH₃ CN HA-227. CH₃ CHF₂ 3-OCH₃ CN H A-228. CH₃ CHF₂ 5-F CN H A-229. CH₃ CHF₂5-CH₃ CN H A-230. CH₃ CHF₂ 5-OCH₃ CN H A-231. CH₃ CF₃ 3-F CN H A-232.CH₃ CF₃ 3-CH₃ CN H A-233. CH₃ CF₃ 3-OCH₃ CN H A-234. CH₃ CF₃ 5-F CN HA-235. CH₃ CF₃ 5-CH₃ CN H A-236. CH₃ CF₃ 5-OCH₃ CN H A-237. CH₃ OCH₂F3-F CN H A-238. CH₃ OCH₂F 3-CH₃ CN H A-239. CH₃ OCH₂F 3-OCH₃ CN H A-240.CH₃ OCH₂F 5-F CN H A-241. CH₃ OCH₂F 5-CH₃ CN H A-242. CH₃ OCH₂F 5-OCH₃CN H A-243. CH₃ OCHF₂ 3-F CN H A-244. CH₃ OCHF₂ 3-CH₃ CN H A-245. CH₃OCHF₂ 3-OCH₃ CN H A-246. CH₃ OCHF₂ 5-F CN H A-247. CH₃ OCHF₂ 5-CH₃ CN HA-248. CH₃ OCHF₂ 5-OCH₃ CN H A-249. CH₃ OCF₃ 3-F CN H A-250. CH₃ OCF₃3-CH₃ CN H A-251. CH₃ OCF₃ 3-OCH₃ CN H A-252. CH₃ OCF₃ 5-F CN H A-253.CH₃ OCF₃ 5-CH₃ CN H A-254. CH₃ OCF₃ 5-OCH₃ CN H A-255. OCH₃ F 3-F CN HA-256. OCH₃ F 3-CH₃ CN H A-257. OCH₃ F 3-OCH₃ CN H A-258. OCH₃ F 5-F CNH A-259. OCH₃ F 5-CH₃ CN H A-260. OCH₃ F 5-OCH₃ CN H A-261. OCH₃ CH₃ 3-FCN H A-262. OCH₃ CH₃ 3-CH₃ CN H A-263. OCH₃ CH₃ 3-OCH₃ CN H A-264. OCH₃CH₃ 5-F CN H A-265. OCH₃ CH₃ 5-CH₃ CN H A-266. OCH₃ CH₃ 5-OCH₃ CN HA-267. OCH₃ OCH₃ 3-F CN H A-268. OCH₃ OCH₃ 3-CH₃ CN H A-269. OCH₃ OCH₃3-OCH₃ CN H A-270. OCH₃ OCH₃ 5-F CN H A-271. OCH₃ OCH₃ 5-CH₃ CN H A-272.OCH₃ OCH₃ 5-OCH₃ CN H A-273. OCH₃ CN 3-F CN H A-274. OCH₃ CN 3-CH₃ CN HA-275. OCH₃ CN 3-OCH₃ CN H A-276. OCH₃ CN 5-F CN H A-277. OCH₃ CN 5-CH₃CN H A-278. OCH₃ CN 5-OCH₃ CN H A-279. OCH₃ CH₂F 3-F CN H A-280. OCH₃CH₂F 3-CH₃ CN H A-281. OCH₃ CH₂F 3-OCH₃ CN H A-282. OCH₃ CH₂F 5-F CN HA-283. OCH₃ CH₂F 5-CH₃ CN H A-284. OCH₃ CH₂F 5-OCH₃ CN H A-285. OCH₃CHF₂ 3-F CN H A-286. OCH₃ CHF₂ 3-CH₃ CN H A-287. OCH₃ CHF₂ 3-OCH₃ CN HA-288. OCH₃ CHF₂ 5-F CN H A-289. OCH₃ CHF₂ 5-CH₃ CN H A-290. OCH₃ CHF₂5-OCH₃ CN H A-291. OCH₃ CF₃ 3-F CN H A-292. OCH₃ CF₃ 3-CH₃ CN H A-293.OCH₃ CF₃ 3-OCH₃ CN H A-294. OCH₃ CF₃ 5-F CN H A-295. OCH₃ CF₃ 5-CH₃ CN HA-296. OCH₃ CF₃ 5-OCH₃ CN H A-297. OCH₃ OCH₂F 3-F CN H A-298. OCH₃ OCH₂F3-CH₃ CN H A-299. OCH₃ OCH₂F 3-OCH₃ CN H A-300. OCH₃ OCH₂F 5-F CN HA-301. OCH₃ OCH₂F 5-CH₃ CN H A-302. OCH₃ OCH₂F 5-OCH₃ CN H A-303. OCH₃OCHF₂ 3-F CN H A-304. OCH₃ OCHF₂ 3-CH₃ CN H A-305. OCH₃ OCHF₂ 3-OCH₃ CNH A-306. OCH₃ OCHF₂ 5-F CN H A-307. OCH₃ OCHF₂ 5-CH₃ CN H A-308. OCH₃OCHF₂ 5-OCH₃ CN H A-309. OCH₃ OCF₃ 3-F CN H A-310. OCH₃ OCF₃ 3-CH₃ CN HA-311. OCH₃ OCF₃ 3-OCH₃ CN H A-312. OCH₃ OCF₃ 5-F CN H A-313. OCH₃ OCF₃5-CH₃ CN H A-314. OCH₃ OCF₃ 5-OCH₃ CN H A-315. CH₂F F 3-F CN H A-316.CH₂F F 3-CH₃ CN H A-317. CH₂F F 3-OCH₃ CN H A-318. CH₂F F 5-F CN HA-319. CH₂F F 5-CH₃ CN H A-320. CH₂F F 5-OCH₃ CN H A-321. CH₂F CH₃ 3-FCN H A-322. CH₂F CH₃ 3-CH₃ CN H A-323. CH₂F CH₃ 3-OCH₃ CN H A-324. CH₂FCH₃ 5-F CN H A-325. CH₂F CH₃ 5-CH₃ CN H A-326. CH₂F CH₃ 5-OCH₃ CN HA-327. CH₂F OCH₃ 3-F CN H A-328. CH₂F OCH₃ 3-CH₃ CN H A-329. CH₂F OCH₃3-OCH₃ CN H A-330. CH₂F OCH₃ 5-F CN H A-331. CH₂F OCH₃ 5-CH₃ CN H A-332.CH₂F OCH₃ 5-OCH₃ CN H A-333. CH₂F CN 3-F CN H A-334. CH₂F CN 3-CH₃ CN HA-335. CH₂F CN 3-OCH₃ CN H A-336. CH₂F CN 5-F CN H A-337. CH₂F CN 5-CH₃CN H A-338. CH₂F CN 5-OCH₃ CN H A-339. CH₂F CH₂F 3-F CN H A-340. CH₂FCH₂F 3-CH₃ CN H A-341. CH₂F CH₂F 3-OCH₃ CN H A-342. CH₂F CH₂F 5-F CN HA-343. CH₂F CH₂F 5-CH₃ CN H A-344. CH₂F CH₂F 5-OCH₃ CN H A-345. CH₂FCHF₂ 3-F CN H A-346. CH₂F CHF₂ 3-CH₃ CN H A-347. CH₂F CHF₂ 3-OCH₃ CN HA-348. CH₂F CHF₂ 5-F CN H A-349. CH₂F CHF₂ 5-CH₃ CN H A-350. CH₂F CHF₂5-OCH₃ CN H A-351. CH₂F CF₃ 3-F CN H A-352. CH₂F CF₃ 3-CH₃ CN H A-353.CH₂F CF₃ 3-OCH₃ CN H A-354. CH₂F CF₃ 5-F CN H A-355. CH₂F CF₃ 5-CH₃ CN HA-356. CH₂F CF₃ 5-OCH₃ CN H A-357. CH₂F OCH₂F 3-F CN H A-358. CH₂F OCH₂F3-CH₃ CN H A-359. CH₂F OCH₂F 3-OCH₃ CN H A-360. CH₂F OCH₂F 5-F CN HA-361. CH₂F OCH₂F 5-CH₃ CN H A-362. CH₂F OCH₂F 5-OCH₃ CN H A-363. CH₂FOCHF₂ 3-F CN H A-364. CH₂F OCHF₂ 3-CH₃ CN H A-365. CH₂F OCHF₂ 3-OCH₃ CNH A-366. CH₂F OCHF₂ 5-F CN H A-367. CH₂F OCHF₂ 5-CH₃ CN H A-368. CH₂FOCHF₂ 5-OCH₃ CN H A-369. CH₂F OCF₃ 3-F CN H A-370. CH₂F OCF₃ 3-CH₃ CN HA-371. CH₂F OCF₃ 3-OCH₃ CN H A-372. CH₂F OCF₃ 5-F CN H A-373. CH₂F OCF₃5-CH₃ CN H A-374. CH₂F OCF₃ 5-OCH₃ CN H A-375. CHF₂ F 3-F CN H A-376.CHF₂ F 3-CH₃ CN H A-377. CHF₂ F 3-OCH₃ CN H A-378. CHF₂ F 5-F CN HA-379. CHF₂ F 5-CH₃ CN H A-380. CHF₂ F 5-OCH₃ CN H A-381. CHF₂ CH₃ 3-FCN H A-382. CHF₂ CH₃ 3-CH₃ CN H A-383. CHF₂ CH₃ 3-OCH₃ CN H A-384. CHF₂CH₃ 5-F CN H A-385. CHF₂ CH₃ 5-CH₃ CN H A-386. CHF₂ CH₃ 5-OCH₃ CN HA-387. CHF₂ OCH₃ 3-F CN H A-388. CHF₂ OCH₃ 3-CH₃ CN H A-389. CHF₂ OCH₃3-OCH₃ CN H A-390. CHF₂ OCH₃ 5-F CN H A-391. CHF₂ OCH₃ 5-CH₃ CN H A-392.CHF₂ OCH₃ 5-OCH₃ CN H A-393. CHF₂ CN 3-F CN H A-394. CHF₂ CN 3-CH₃ CN HA-395. CHF₂ CN 3-OCH₃ CN H A-396. CHF₂ CN 5-F CN H A-397. CHF₂ CN 5-CH₃CN H A-398. CHF₂ CN 5-OCH₃ CN H A-399. CHF₂ CH₂F 3-F CN H A-400. CHF₂CH₂F 3-CH₃ CN H A-401. CHF₂ CH₂F 3-OCH₃ CN H A-402. CHF₂ CH₂F 5-F CN HA-403. CHF₂ CH₂F 5-CH₃ CN H A-404. CHF₂ CH₂F 5-OCH₃ CN H A-405. CHF₂CHF₂ 3-F CN H A-406. CHF₂ CHF₂ 3-CH₃ CN H A-407. CHF₂ CHF₂ 3-OCH₃ CN HA-408. CHF₂ CHF₂ 5-F CN H A-409. CHF₂ CHF₂ 5-CH₃ CN H A-410. CHF₂ CHF₂5-OCH₃ CN H A-411. CHF₂ CF₃ 3-F CN H A-412. CHF₂ CF₃ 3-CH₃ CN H A-413.CHF₂ CF₃ 3-OCH₃ CN H A-414. CHF₂ CF₃ 5-F CN H A-415. CHF₂ CF₃ 5-CH₃ CN HA-416. CHF₂ CF₃ 5-OCH₃ CN H A-417. CHF₂ OCH₂F 3-F CN H A-418. CHF₂ OCH₂F3-CH₃ CN H A-419. CHF₂ OCH₂F 3-OCH₃ CN H A-420. CHF₂ OCH₂F 5-F CN HA-421. CHF₂ OCH₂F 5-CH₃ CN H A-422. CHF₂ OCH₂F 5-OCH₃ CN H A-423. CHF₂OCHF₂ 3-F CN H A-424. CHF₂ OCHF₂ 3-CH₃ CN H A-425. CHF₂ OCHF₂ 3-OCH₃ CNH A-426. CHF₂ OCHF₂ 5-F CN H A-427. CHF₂ OCHF₂ 5-CH₃ CN H A-428. CHF₂OCHF₂ 5-OCH₃ CN H A-429. CHF₂ OCF₃ 3-F CN H A-430. CHF₂ OCF₃ 3-CH₃ CN HA-431. CHF₂ OCF₃ 3-OCH₃ CN H A-432. CHF₂ OCF₃ 5-F CN H A-433. CHF₂ OCF₃5-CH₃ CN H A-434. CHF₂ OCF₃ 5-OCH₃ CN H A-435. CF₃ F 3-F CN H A-436. CF₃F 3-CH₃ CN H A-437. CF₃ F 3-OCH₃ CN H A-438. CF₃ F 5-F CN H A-439. CF₃ F5-CH₃ CN H A-440. CF₃ F 5-OCH₃ CN H A-441. CF₃ CH₃ 3-F CN H A-442. CF₃CH₃ 3-CH₃ CN H A-443. CF₃ CH₃ 3-OCH₃ CN H A-444. CF₃ CH₃ 5-F CN H A-445.CF₃ CH₃ 5-CH₃ CN H A-446. CF₃ CH₃ 5-OCH₃ CN H A-447. CF₃ OCH₃ 3-F CN HA-448. CF₃ OCH₃ 3-CH₃ CN H A-449. CF₃ OCH₃ 3-OCH₃ CN H A-450. CF₃ OCH₃5-F CN H A-451. CF₃ OCH₃ 5-CH₃ CN H A-452. CF₃ OCH₃ 5-OCH₃ CN H A-453.CF₃ CN 3-F CN H A-454. CF₃ CN 3-CH₃ CN H A-455. CF₃ CN 3-OCH₃ CN HA-456. CF₃ CN 5-F CN H A-457. CF₃ CN 5-CH₃ CN H A-458. CF₃ CN 5-OCH₃ CNH A-459. CF₃ CH₂F 3-F CN H A-460. CF₃ CH₂F 3-CH₃ CN H A-461. CF₃ CH₂F3-OCH₃ CN H A-462. CF₃ CH₂F 5-F CN H A-463. CF₃ CH₂F 5-CH₃ CN H A-464.CF₃ CH₂F 5-OCH₃ CN H A-465. CF₃ CHF₂ 3-F CN H A-466. CF₃ CHF₂ 3-CH₃ CN HA-467. CF₃ CHF₂ 3-OCH₃ CN H A-468. CF₃ CHF₂ 5-F CN H A-469. CF₃ CHF₂5-CH₃ CN H A-470. CF₃ CHF₂ 5-OCH₃ CN H A-471. CF₃ CF₃ 3-F CN H A-472.CF₃ CF₃ 3-CH₃ CN H A-473. CF₃ CF₃ 3-OCH₃ CN H A-474. CF₃ CF₃ 5-F CN HA-475. CF₃ CF₃ 5-CH₃ CN H A-476. CF₃ CF₃ 5-OCH₃ CN H A-477. CF₃ OCH₂F3-F CN H A-478. CF₃ OCH₂F 3-CH₃ CN H A-479. CF₃ OCH₂F 3-OCH₃ CN H A-480.CF₃ OCH₂F 5-F CN H A-481. CF₃ OCH₂F 5-CH₃ CN H A-482. CF₃ OCH₂F 5-OCH₃CN H A-483. CF₃ OCHF₂ 3-F CN H A-484. CF₃ OCHF₂ 3-CH₃ CN H A-485. CF₃OCHF₂ 3-OCH₃ CN H A-486. CF₃ OCHF₂ 5-F CN H A-487. CF₃ OCHF₂ 5-CH₃ CN HA-488. CF₃ OCHF₂ 5-OCH₃ CN H A-489. CF₃ OCF₃ 3-F CN H A-490. CF₃ OCF₃3-CH₃ CN H A-491. CF₃ OCF₃ 3-OCH₃ CN H A-492. CF₃ OCF₃ 5-F CN H A-493.CF₃ OCF₃ 5-CH₃ CN H A-494. CF₃ OCF₃ 5-OCH₃ CN H A-495. OCH₂F F 3-F CN HA-496. OCH₂F F 3-CH₃ CN H A-497. OCH₂F F 3-OCH₃ CN H A-498. OCH₂F F 5-FCN H A-499. OCH₂F F 5-CH₃ CN H A-500. OCH₂F F 5-OCH₃ CN H A-501. OCH₂FCH₃ 3-F CN H A-502. OCH₂F CH₃ 3-CH₃ CN H A-503. OCH₂F CH₃ 3-OCH₃ CN HA-504. OCH₂F CH₃ 5-F CN H A-505. OCH₂F CH₃ 5-CH₃ CN H A-506. OCH₂F CH₃5-OCH₃ CN H A-507. OCH₂F OCH₃ 3-F CN H A-508. OCH₂F OCH₃ 3-CH₃ CN HA-509. OCH₂F OCH₃ 3-OCH₃ CN H A-510. OCH₂F OCH₃ 5-F CN H A-511. OCH₂FOCH₃ 5-CH₃ CN H A-512. OCH₂F OCH₃ 5-OCH₃ CN H A-513. OCH₂F CN 3-F CN HA-514. OCH₂F CN 3-CH₃ CN H A-515. OCH₂F CN 3-OCH₃ CN H A-516. OCH₂F CN5-F CN H A-517. OCH₂F CN 5-CH₃ CN H A-518. OCH₂F CN 5-OCH₃ CN H A-519.OCH₂F CH₂F 3-F CN H A-520. OCH₂F CH₂F 3-CH₃ CN H A-521. OCH₂F CH₂F3-OCH₃ CN H A-522. OCH₂F CH₂F 5-F CN H A-523. OCH₂F CH₂F 5-CH₃ CN HA-524. OCH₂F CH₂F 5-OCH₃ CN H A-525. OCH₂F CHF₂ 3-F CN H A-526. OCH₂FCHF₂ 3-CH₃ CN H A-527. OCH₂F CHF₂ 3-OCH₃ CN H A-528. OCH₂F CHF₂ 5-F CN HA-529. OCH₂F CHF₂ 5-CH₃ CN H A-530. OCH₂F CHF₂ 5-OCH₃ CN H A-531. OCH₂FCF₃ 3-F CN H A-532. OCH₂F CF₃ 3-CH₃ CN H A-533. OCH₂F CF₃ 3-OCH₃ CN HA-534. OCH₂F CF₃ 5-F CN H A-535. OCH₂F CF₃ 5-CH₃ CN H A-536. OCH₂F CF₃5-OCH₃ CN H A-537. OCH₂F OCH₂F 3-F CN H A-538. OCH₂F OCH₂F 3-CH₃ CN HA-539. OCH₂F OCH₂F 3-OCH₃ CN H A-540. OCH₂F OCH₂F 5-F CN H A-541. OCH₂FOCH₂F 5-CH₃ CN H A-542. OCH₂F OCH₂F 5-OCH₃ CN H A-543. OCH₂F OCHF₂ 3-FCN H A-544. OCH₂F OCHF₂ 3-CH₃ CN H A-545. OCH₂F OCHF₂ 3-OCH₃ CN H A-546.OCH₂F OCHF₂ 5-F CN H A-547. OCH₂F OCHF₂ 5-CH₃ CN H A-548. OCH₂F OCHF₂5-OCH₃ CN H A-549. OCH₂F OCF₃ 3-F CN H A-550. OCH₂F OCF₃ 3-CH₃ CN HA-551. OCH₂F OCF₃ 3-OCH₃ CN H A-552. OCH₂F OCF₃ 5-F CN H A-553. OCH₂FOCF₃ 5-CH₃ CN H A-554. OCH₂F OCF₃ 5-OCH₃ CN H A-555. OCHF₂ F 3-F CN HA-556. OCHF₂ F 3-CH₃ CN H A-557. OCHF₂ F 3-OCH₃ CN H A-558. OCHF₂ F 5-FCN H A-559. OCHF₂ F 5-CH₃ CN H A-560. OCHF₂ F 5-OCH₃ CN H A-561. OCHF₂CH₃ 3-F CN H A-562. OCHF₂ CH₃ 3-CH₃ CN H A-563. OCHF₂ CH₃ 3-OCH₃ CN HA-564. OCHF₂ CH₃ 5-F CN H A-565. OCHF₂ CH₃ 5-CH₃ CN H A-566. OCHF₂ CH₃5-OCH₃ CN H A-567. OCHF₂ OCH₃ 3-F CN H A-568. OCHF₂ OCH₃ 3-CH₃ CN HA-569. OCHF₂ OCH₃ 3-OCH₃ CN H A-570. OCHF₂ OCH₃ 5-F CN H A-571. OCHF₂OCH₃ 5-CH₃ CN H A-572. OCHF₂ OCH₃ 5-OCH₃ CN H A-573. OCHF₂ CN 3-F CN HA-574. OCHF₂ CN 3-CH₃ CN H A-575. OCHF₂ CN 3-OCH₃ CN H A-576. OCHF₂ CN5-F CN H A-577. OCHF₂ CN 5-CH₃ CN H A-578. OCHF₂ CN 5-OCH₃ CN H A-579.OCHF₂ CH₂F 3-F CN H A-580. OCHF₂ CH₂F 3-CH₃ CN H A-581. OCHF₂ CH₂F3-OCH₃ CN H A-582. OCHF₂ CH₂F 5-F CN H A-583. OCHF₂ CH₂F 5-CH₃ CN HA-584. OCHF₂ CH₂F 5-OCH₃ CN H A-585. OCHF₂ CHF₂ 3-F CN H A-586. OCHF₂CHF₂ 3-CH₃ CN H A-587. OCHF₂ CHF₂ 3-OCH₃ CN H A-588. OCHF₂ CHF₂ 5-F CN HA-589. OCHF₂ CHF₂ 5-CH₃ CN H A-590. OCHF₂ CHF₂ 5-OCH₃ CN H A-591. OCHF₂CF₃ 3-F CN H A-592. OCHF₂ CF₃ 3-CH₃ CN H A-593. OCHF₂ CF₃ 3-OCH₃ CN HA-594. OCHF₂ CF₃ 5-F CN H A-595. OCHF₂ CF₃ 5-CH₃ CN H A-596. OCHF₂ CF₃5-OCH₃ CN H A-597. OCHF₂ OCH₂F 3-F CN H A-598. OCHF₂ OCH₂F 3-CH₃ CN HA-599. OCHF₂ OCH₂F 3-OCH₃ CN H A-600. OCHF₂ OCH₂F 5-F CN H A-601. OCHF₂OCH₂F 5-CH₃ CN H A-602. OCHF₂ OCH₂F 5-OCH₃ CN H A-603. OCHF₂ OCHF₂ 3-FCN H A-604. OCHF₂ OCHF₂ 3-CH₃ CN H A-605. OCHF₂ OCHF₂ 3-OCH₃ CN H A-606.OCHF₂ OCHF₂ 5-F CN H A-607. OCHF₂ OCHF₂ 5-CH₃ CN H A-608. OCHF₂ OCHF₂5-OCH₃ CN H A-609. OCHF₂ OCF₃ 3-F CN H A-610. OCHF₂ OCF₃ 3-CH₃ CN HA-611. OCHF₂ OCF₃ 3-OCH₃ CN H A-612. OCHF₂ OCF₃ 5-F CN H A-613. OCHF₂OCF₃ 5-CH₃ CN H A-614. OCHF₂ OCF₃ 5-OCH₃ CN H A-615. OCF₃ F 3-F CN HA-616. OCF₃ F 3-CH₃ CN H A-617. OCF₃ F 3-OCH₃ CN H A-618. OCF₃ F 5-F CNH A-619. OCF₃ F 5-CH₃ CN H A-620. OCF₃ F 5-OCH₃ CN H A-621. OCF₃ CH₃ 3-FCN H A-622. OCF₃ CH₃ 3-CH₃ CN H A-623. OCF₃ CH₃ 3-OCH₃ CN H A-624. OCF₃CH₃ 5-F CN H A-625. OCF₃ CH₃ 5-CH₃ CN H A-626. OCF₃ CH₃ 5-OCH₃ CN HA-627. OCF₃ OCH₃ 3-F CN H A-628. OCF₃ OCH₃ 3-CH₃ CN H A-629. OCF₃ OCH₃3-OCH₃ CN H A-630. OCF₃ OCH₃ 5-F CN H A-631. OCF₃ OCH₃ 5-CH₃ CN H A-632.OCF₃ OCH₃ 5-OCH₃ CN H A-633. OCF₃ CN 3-F CN H A-634. OCF₃ CN 3-CH₃ CN HA-635. OCF₃ CN 3-OCH₃ CN H A-636. OCF₃ CN 5-F CN H A-637. OCF₃ CN 5-CH₃CN H A-638. OCF₃ CN 5-OCH₃ CN H A-639. OCF₃ CH₂F 3-F CN H A-640. OCF₃CH₂F 3-CH₃ CN H A-641. OCF₃ CH₂F 3-OCH₃ CN H A-642. OCF₃ CH₂F 5-F CN HA-643. OCF₃ CH₂F 5-CH₃ CN H A-644. OCF₃ CH₂F 5-OCH₃ CN H A-645. OCF₃CHF₂ 3-F CN H A-646. OCF₃ CHF₂ 3-CH₃ CN H A-647. OCF₃ CHF₂ 3-OCH₃ CN HA-648. OCF₃ CHF₂ 5-F CN H A-649. OCF₃ CHF₂ 5-CH₃ CN H A-650. OCF₃ CHF₂5-OCH₃ CN H A-651. OCF₃ CF₃ 3-F CN H A-652. OCF₃ CF₃ 3-CH₃ CN H A-653.OCF₃ CF₃ 3-OCH₃ CN H A-654. OCF₃ CF₃ 5-F CN H A-655. OCF₃ CF₃ 5-CH₃ CN HA-656. OCF₃ CF₃ 5-OCH₃ CN H A-657. OCF₃ OCH₂F 3-F CN H A-658. OCF₃ OCH₂F3-CH₃ CN H A-659. OCF₃ OCH₂F 3-OCH₃ CN H A-660. OCF₃ OCH₂F 5-F CN HA-661. OCF₃ OCH₂F 5-CH₃ CN H A-662. OCF₃ OCH₂F 5-OCH₃ CN H A-663. OCF₃OCHF₂ 3-F CN H A-664. OCF₃ OCHF₂ 3-CH₃ CN H A-665. OCF₃ OCHF₂ 3-OCH₃ CNH A-666. OCF₃ OCHF₂ 5-F CN H A-667. OCF₃ OCHF₂ 5-CH₃ CN H A-668. OCF₃OCHF₂ 5-OCH₃ CN H A-669. OCF₃ OCF₃ 3-F CN H A-670. OCF₃ OCF₃ 3-CH₃ CN HA-671. OCF₃ OCF₃ 3-OCH₃ CN H A-672. OCF₃ OCF₃ 5-F CN H A-673. OCF₃ OCF₃5-CH₃ CN H A-674. OCF₃ OCF₃ 5-OCH₃ CN H A-675. H H H F H A-676. F H H FH A-677. CH₃ H H F H A-678. OCH₃ H H F H A-679. CH₂F H H F H A-680. CHF₂H H F H A-681. CF₃ H H F H A-682. OCH₂F H H F H A-683. OCHF₂ H H F HA-684. OCF₃ H H F H A-685. H F H F H A-686. H CH₃ H F H A-687. H OCH₃ HF H A-688. H CN H F H A-689. H CH₂F H F H A-690. H CHF₂ H F H A-691. HCF₃ H F H A-692. H OCH₂F H F H A-693. H OCHF₂ H F H A-694. H OCF₃ H F HA-695. H H 3-F F H A-696. H H 3-CH₃ F H A-697. H H 3-OCH₃ F H A-698. H H5-F F H A-699. H H 5-CH₃ F H A-700. H H 5-OCH₃ F H A-701. F F H F HA-702. F CH₃ H F H A-703. F OCH₃ H F H A-704. F CN H F H A-705. F CH₂F HF H A-706. F CHF₂ H F H A-707. F CF₃ H F H A-708. F OCH₂F H F H A-709. FOCHF₂ H F H A-710. F OCF₃ H F H A-711. F H 3-F F H A-712. F H 3-CH₃ F HA-713. F H 3-OCH₃ F H A-714. F H 5-F F H A-715. F H 5-CH₃ F H A-716. F H5-OCH₃ F H A-717. CH₃ F H F H A-718. CH₃ CH₃ H F H A-719. CH₃ OCH₃ H F HA-720. CH₃ CN H F H A-721. CH₃ CH₂F H F H A-722. CH₃ CHF₂ H F H A-723.CH₃ CF₃ H F H A-724. CH₃ OCH₂F H F H A-725. CH₃ OCHF₂ H F H A-726. CH₃OCF₃ H F H A-727. CH₃ H 3-F F H A-728. CH₃ H 3-CH₃ F H A-729. CH₃ H3-OCH₃ F H A-730. CH₃ H 5-F F H A-731. CH₃ H 5-CH₃ F H A-732. CH₃ H5-OCH₃ F H A-733. OCH₃ F H F H A-734. OCH₃ CH₃ H F H A-735. OCH₃ OCH₃ HF H A-736. OCH₃ CN H F H A-737. OCH₃ CH₂F H F H A-738. OCH₃ CHF₂ H F HA-739. OCH₃ CF₃ H F H A-740. OCH₃ OCH₂F H F H A-741. OCH₃ OCHF₂ H F HA-742. OCH₃ OCF₃ H F H A-743. OCH₃ H 3-F F H A-744. OCH₃ H 3-CH₃ F HA-745. OCH₃ H 3-OCH₃ F H A-746. OCH₃ H 5-F F H A-747. OCH₃ H 5-CH₃ F HA-748. OCH₃ H 5-OCH₃ F H A-749. H F 3-F F H A-750. H F 3-CH₃ F H A-751.H F 3-OCH₃ F H A-752. H F 5-F F H A-753. H F 5-CH₃ F H A-754. H F 5-OCH₃F H A-755. H CH₃ 3-F F H A-756. H CH₃ 3-CH₃ F H A-757. H CH₃ 3-OCH₃ F HA-758. H CH₃ 5-F F H A-759. H CH₃ 5-CH₃ F H A-760. H CH₃ 5-OCH₃ F HA-761. H OCH₃ 3-F F H A-762. H OCH₃ 3-CH₃ F H A-763. H OCH₃ 3-OCH₃ F HA-764. H OCH₃ 5-F F H A-765. H OCH₃ 5-CH₃ F H A-766. H OCH₃ 5-OCH₃ F HA-767. H CN 3-F F H A-768. H CN 3-CH₃ F H A-769. H CN 3-OCH₃ F H A-770.H CN 5-F F H A-771. H CN 5-CH₃ F H A-772. H CN 5-OCH₃ F H A-773. H CH₂F3-F F H A-774. H CH₂F 3-CH₃ F H A-775. H CH₂F 3-OCH₃ F H A-776. H CH₂F5-F F H A-777. H CH₂F 5-CH₃ F H A-778. H CH₂F 5-OCH₃ F H A-779. H CHF₂3-F F H A-780. H CHF₂ 3-CH₃ F H A-781. H CHF₂ 3-OCH₃ F H A-782. H CHF₂5-F F H A-783. H CHF₂ 5-CH₃ F H A-784. H CHF₂ 5-OCH₃ F H A-785. H CF₃3-F F H A-786. H CF₃ 3-CH₃ F H A-787. H CF₃ 3-OCH₃ F H A-788. H CF₃ 5-FF H A-789. H CF₃ 5-CH₃ F H A-790. H CF₃ 5-OCH₃ F H A-791. H OCH₂F 3-F FH A-792. H OCH₂F 3-CH₃ F H A-793. H OCH₂F 3-OCH₃ F H A-794. H OCH₂F 5-FF H A-795. H OCH₂F 5-CH₃ F H A-796. H OCH₂F 5-OCH₃ F H A-797. H OCHF₂3-F F H A-798. H OCHF₂ 3-CH₃ F H A-799. H OCHF₂ 3-OCH₃ F H A-800. HOCHF₂ 5-F F H A-801. H OCHF₂ 5-CH₃ F H A-802. H OCHF₂ 5-OCH₃ F H A-803.H OCF₃ 3-F F H A-804. H OCF₃ 3-CH₃ F H A-805. H OCF₃ 3-OCH₃ F H A-806. HOCF₃ 5-F F H A-807. H OCF₃ 5-CH₃ F H A-808. H OCF₃ 5-OCH₃ F H A-809. F F3-F F H A-810. F F 3-CH₃ F H A-811. F F 3-OCH₃ F H A-812. F F 5-F F HA-813. F F 5-CH₃ F H A-814. F F 5-OCH₃ F H A-815. F CH₃ 3-F F H A-816. FCH₃ 3-CH₃ F H A-817. F CH₃ 3-OCH₃ F H A-818. F CH₃ 5-F F H A-819. F CH₃5-CH₃ F H A-820. F CH₃ 5-OCH₃ F H A-821. F OCH₃ 3-F F H A-822. F OCH₃3-CH₃ F H A-823. F OCH₃ 3-OCH₃ F H A-824. F OCH₃ 5-F F H A-825. F OCH₃5-CH₃ F H A-826. F OCH₃ 5-OCH₃ F H A-827. F CN 3-F F H A-828. F CN 3-CH₃F H A-829. F CN 3-OCH₃ F H A-830. F CN 5-F F H A-831. F CN 5-CH₃ F HA-832. F CN 5-OCH₃ F H A-833. F CH₂F 3-F F H A-834. F CH₂F 3-CH₃ F HA-835. F CH₂F 3-OCH₃ F H A-836. F CH₂F 5-F F H A-837. F CH₂F 5-CH₃ F HA-838. F CH₂F 5-OCH₃ F H A-839. F CHF₂ 3-F F H A-840. F CHF₂ 3-CH₃ F HA-841. F CHF₂ 3-OCH₃ F H A-842. F CHF₂ 5-F F H A-843. F CHF₂ 5-CH₃ F HA-844. F CHF₂ 5-OCH₃ F H A-845. F CF₃ 3-F F H A-846. F CF₃ 3-CH₃ F HA-847. F CF₃ 3-OCH₃ F H A-848. F CF₃ 5-F F H A-849. F CF₃ 5-CH₃ F HA-850. F CF₃ 5-OCH₃ F H A-851. F OCH₂F 3-F F H A-852. F OCH₂F 3-CH₃ F HA-853. F OCH₂F 3-OCH₃ F H A-854. F OCH₂F 5-F F H A-855. F OCH₂F 5-CH₃ FH A-856. F OCH₂F 5-OCH₃ F H A-857. F OCHF₂ 3-F F H A-858. F OCHF₂ 3-CH₃F H A-859. F OCHF₂ 3-OCH₃ F H A-860. F OCHF₂ 5-F F H A-861. F OCHF₂5-CH₃ F H A-862. F OCHF₂ 5-OCH₃ F H A-863. F OCF₃ 3-F F H A-864. F OCF₃3-CH₃ F H A-865. F OCF₃ 3-OCH₃ F H A-866. F OCF₃ 5-F F H A-867. F OCF₃5-CH₃ F H A-868. F OCF₃ 5-OCH₃ F H A-869. CH₃ F 3-F F H A-870. CH₃ F3-CH₃ F H A-871. CH₃ F 3-OCH₃ F H A-872. CH₃ F 5-F F H A-873. CH₃ F5-CH₃ F H A-874. CH₃ F 5-OCH₃ F H A-875. CH₃ CH₃ 3-F F H A-876. CH₃ CH₃3-CH₃ F H A-877. CH₃ CH₃ 3-OCH₃ F H A-878. CH₃ CH₃ 5-F F H A-879. CH₃CH₃ 5-CH₃ F H A-880. CH₃ CH₃ 5-OCH₃ F H A-881. CH₃ OCH₃ 3-F F H A-882.CH₃ OCH₃ 3-CH₃ F H A-883. CH₃ OCH₃ 3-OCH₃ F H A-884. CH₃ OCH₃ 5-F F HA-885. CH₃ OCH₃ 5-CH₃ F H A-886. CH₃ OCH₃ 5-OCH₃ F H A-887. CH₃ CN 3-F FH A-888. CH₃ CN 3-CH₃ F H A-889. CH₃ CN 3-OCH₃ F H A-890. CH₃ CN 5-F F HA-891. CH₃ CN 5-CH₃ F H A-892. CH₃ CN 5-OCH₃ F H A-893. CH₃ CH₂F 3-F F HA-894. CH₃ CH₂F 3-CH₃ F H A-895. CH₃ CH₂F 3-OCH₃ F H A-896. CH₃ CH₂F 5-FF H A-897. CH₃ CH₂F 5-CH₃ F H A-898. CH₃ CH₂F 5-OCH₃ F H A-899. CH₃ CHF₂3-F F H A-900. CH₃ CHF₂ 3-CH₃ F H A-901. CH₃ CHF₂ 3-OCH₃ F H A-902. CH₃CHF₂ 5-F F H A-903. CH₃ CHF₂ 5-CH₃ F H A-904. CH₃ CHF₂ 5-OCH₃ F H A-905.CH₃ CF₃ 3-F F H A-906. CH₃ CF₃ 3-CH₃ F H A-907. CH₃ CF₃ 3-OCH₃ F HA-908. CH₃ CF₃ 5-F F H A-909. CH₃ CF₃ 5-CH₃ F H A-910. CH₃ CF₃ 5-OCH₃ FH A-911. CH₃ OCH₂F 3-F F H A-912. CH₃ OCH₂F 3-CH₃ F H A-913. CH₃ OCH₂F3-OCH₃ F H A-914. CH₃ OCH₂F 5-F F H A-915. CH₃ OCH₂F 5-CH₃ F H A-916.CH₃ OCH₂F 5-OCH₃ F H A-917. CH₃ OCHF₂ 3-F F H A-918. CH₃ OCHF₂ 3-CH₃ F HA-919. CH₃ OCHF₂ 3-OCH₃ F H A-920. CH₃ OCHF₂ 5-F F H A-921. CH₃ OCHF₂5-CH₃ F H A-922. CH₃ OCHF₂ 5-OCH₃ F H A-923. CH₃ OCF₃ 3-F F H A-924. CH₃OCF₃ 3-CH₃ F H A-925. CH₃ OCF₃ 3-OCH₃ F H A-926. CH₃ OCF₃ 5-F F H A-927.CH₃ OCF₃ 5-CH₃ F H A-928. CH₃ OCF₃ 5-OCH₃ F H A-929. OCH₃ F 3-F F HA-930. OCH₃ F 3-CH₃ F H A-931. OCH₃ F 3-OCH₃ F H A-932. OCH₃ F 5-F F HA-933. OCH₃ F 5-CH₃ F H A-934. OCH₃ F 5-OCH₃ F H A-935. OCH₃ CH₃ 3-F F HA-936. OCH₃ CH₃ 3-CH₃ F H A-937. OCH₃ CH₃ 3-OCH₃ F H A-938. OCH₃ CH₃ 5-FF H A-939. OCH₃ CH₃ 5-CH₃ F H A-940. OCH₃ CH₃ 5-OCH₃ F H A-941. OCH₃OCH₃ 3-F F H A-942. OCH₃ OCH₃ 3-CH₃ F H A-943. OCH₃ OCH₃ 3-OCH₃ F HA-944. OCH₃ OCH₃ 5-F F H A-945. OCH₃ OCH₃ 5-CH₃ F H A-946. OCH₃ OCH₃5-OCH₃ F H A-947. OCH₃ CN 3-F F H A-948. OCH₃ CN 3-CH₃ F H A-949. OCH₃CN 3-OCH₃ F H A-950. OCH₃ CN 5-F F H A-951. OCH₃ CN 5-CH₃ F H A-952.OCH₃ CN 5-OCH₃ F H A-953. OCH₃ CH₂F 3-F F H A-954. OCH₃ CH₂F 3-CH₃ F HA-955. OCH₃ CH₂F 3-OCH₃ F H A-956. OCH₃ CH₂F 5-F F H A-957. OCH₃ CH₂F5-CH₃ F H A-958. OCH₃ CH₂F 5-OCH₃ F H A-959. OCH₃ CHF₂ 3-F F H A-960.OCH₃ CHF₂ 3-CH₃ F H A-961. OCH₃ CHF₂ 3-OCH₃ F H A-962. OCH₃ CHF₂ 5-F F HA-963. OCH₃ CHF₂ 5-CH₃ F H A-964. OCH₃ CHF₂ 5-OCH₃ F H A-965. OCH₃ CF₃3-F F H A-966. OCH₃ CF₃ 3-CH₃ F H A-967. OCH₃ CF₃ 3-OCH₃ F H A-968. OCH₃CF₃ 5-F F H A-969. OCH₃ CF₃ 5-CH₃ F H A-970. OCH₃ CF₃ 5-OCH₃ F H A-971.OCH₃ OCH₂F 3-F F H A-972. OCH₃ OCH₂F 3-CH₃ F H A-973. OCH₃ OCH₂F 3-OCH₃F H A-974. OCH₃ OCH₂F 5-F F H A-975. OCH₃ OCH₂F 5-CH₃ F H A-976. OCH₃OCH₂F 5-OCH₃ F H A-977. OCH₃ OCHF₂ 3-F F H A-978. OCH₃ OCHF₂ 3-CH₃ F HA-979. OCH₃ OCHF₂ 3-OCH₃ F H A-980. OCH₃ OCHF₂ 5-F F H A-981. OCH₃ OCHF₂5-CH₃ F H A-982. OCH₃ OCHF₂ 5-OCH₃ F H A-983. OCH₃ OCF₃ 3-F F H A-984.OCH₃ OCF₃ 3-CH₃ F H A-985. OCH₃ OCF₃ 3-OCH₃ F H A-986. OCH₃ OCF₃ 5-F F HA-987. OCH₃ OCF₃ 5-CH₃ F H A-988. OCH₃ OCF₃ 5-OCH₃ F H A-989. CH₂F F 3-FF H A-990. CH₂F F 3-CH₃ F H A-991. CH₂F F 3-OCH₃ F H A-992. CH₂F F 5-F FH A-993. CH₂F F 5-CH₃ F H A-994. CH₂F F 5-OCH₃ F H A-995. CH₂F CH₃ 3-F FH A-996. CH₂F CH₃ 3-CH₃ F H A-997. CH₂F CH₃ 3-OCH₃ F H A-998. CH₂F CH₃5-F F H A-999. CH₂F CH₃ 5-CH₃ F H A-1000. CH₂F CH₃ 5-OCH₃ F H A-1001.CH₂F OCH₃ 3-F F H A-1002. CH₂F OCH₃ 3-CH₃ F H A-1003. CH₂F OCH₃ 3-OCH₃ FH A-1004. CH₂F OCH₃ 5-F F H A-1005. CH₂F OCH₃ 5-CH₃ F H A-1006. CH₂FOCH₃ 5-OCH₃ F H A-1007. CH₂F CN 3-F F H A-1008. CH₂F CN 3-CH₃ F HA-1009. CH₂F CN 3-OCH₃ F H A-1010. CH₂F CN 5-F F H A-1011. CH₂F CN 5-CH₃F H A-1012. CH₂F CN 5-OCH₃ F H A-1013. CH₂F CH₂F 3-F F H A-1014. CH₂FCH₂F 3-CH₃ F H A-1015. CH₂F CH₂F 3-OCH₃ F H A-1016. CH₂F CH₂F 5-F F HA-1017. CH₂F CH₂F 5-CH₃ F H A-1018. CH₂F CH₂F 5-OCH₃ F H A-1019. CH₂FCHF₂ 3-F F H A-1020. CH₂F CHF₂ 3-CH₃ F H A-1021. CH₂F CHF₂ 3-OCH₃ F HA-1022. CH₂F CHF₂ 5-F F H A-1023. CH₂F CHF₂ 5-CH₃ F H A-1024. CH₂F CHF₂5-OCH₃ F H A-1025. CH₂F CF₃ 3-F F H A-1026. CH₂F CF₃ 3-CH₃ F H A-1027.CH₂F CF₃ 3-OCH₃ F H A-1028. CH₂F CF₃ 5-F F H A-1029. CH₂F CF₃ 5-CH₃ F HA-1030. CH₂F CF₃ 5-OCH₃ F H A-1031. CH₂F OCH₂F 3-F F H A-1032. CH₂FOCH₂F 3-CH₃ F H A-1033. CH₂F OCH₂F 3-OCH₃ F H A-1034. CH₂F OCH₂F 5-F F HA-1035. CH₂F OCH₂F 5-CH₃ F H A-1036. CH₂F OCH₂F 5-OCH₃ F H A-1037. CH₂FOCHF₂ 3-F F H A-1038. CH₂F OCHF₂ 3-CH₃ F H A-1039. CH₂F OCHF₂ 3-OCH₃ F HA-1040. CH₂F OCHF₂ 5-F F H A-1041. CH₂F OCHF₂ 5-CH₃ F H A-1042. CH₂FOCHF₂ 5-OCH₃ F H A-1043. CH₂F OCF₃ 3-F F H A-1044. CH₂F OCF₃ 3-CH₃ F HA-1045. CH₂F OCF₃ 3-OCH₃ F H A-1046. CH₂F OCF₃ 5-F F H A-1047. CH₂F OCF₃5-CH₃ F H A-1048. CH₂F OCF₃ 5-OCH₃ F H A-1049. CHF₂ F 3-F F H A-1050.CHF₂ F 3-CH₃ F H A-1051. CHF₂ F 3-OCH₃ F H A-1052. CHF₂ F 5-F F HA-1053. CHF₂ F 5-CH₃ F H A-1054. CHF₂ F 5-OCH₃ F H A-1055. CHF₂ CH₃ 3-FF H A-1056. CHF₂ CH₃ 3-CH₃ F H A-1057. CHF₂ CH₃ 3-OCH₃ F H A-1058. CHF₂CH₃ 5-F F H A-1059. CHF₂ CH₃ 5-CH₃ F H A-1060. CHF₂ CH₃ 5-OCH₃ F HA-1061. CHF₂ OCH₃ 3-F F H A-1062. CHF₂ OCH₃ 3-CH₃ F H A-1063. CHF₂ OCH₃3-OCH₃ F H A-1064. CHF₂ OCH₃ 5-F F H A-1065. CHF₂ OCH₃ 5-CH₃ F H A-1066.CHF₂ OCH₃ 5-OCH₃ F H A-1067. CHF₂ CN 3-F F H A-1068. CHF₂ CN 3-CH₃ F HA-1069. CHF₂ CN 3-OCH₃ F H A-1070. CHF₂ CN 5-F F H A-1071. CHF₂ CN 5-CH₃F H A-1072. CHF₂ CN 5-OCH₃ F H A-1073. CHF₂ CH₂F 3-F F H A-1074. CHF₂CH₂F 3-CH₃ F H A-1075. CHF₂ CH₂F 3-OCH₃ F H A-1076. CHF₂ CH₂F 5-F F HA-1077. CHF₂ CH₂F 5-CH₃ F H A-1078. CHF₂ CH₂F 5-OCH₃ F H A-1079. CHF₂CHF₂ 3-F F H A-1080. CHF₂ CHF₂ 3-CH₃ F H A-1081. CHF₂ CHF₂ 3-OCH₃ F HA-1082. CHF₂ CHF₂ 5-F F H A-1083. CHF₂ CHF₂ 5-CH₃ F H A-1084. CHF₂ CHF₂5-OCH₃ F H A-1085. CHF₂ CF₃ 3-F F H A-1086. CHF₂ CF₃ 3-CH₃ F H A-1087.CHF₂ CF₃ 3-OCH₃ F H A-1088. CHF₂ CF₃ 5-F F H A-1089. CHF₂ CF₃ 5-CH₃ F HA-1090. CHF₂ CF₃ 5-OCH₃ F H A-1091. CHF₂ OCH₂F 3-F F H A-1092. CHF₂OCH₂F 3-CH₃ F H A-1093. CHF₂ OCH₂F 3-OCH₃ F H A-1094. CHF₂ OCH₂F 5-F F HA-1095. CHF₂ OCH₂F 5-CH₃ F H A-1096. CHF₂ OCH₂F 5-OCH₃ F H A-1097. CHF₂OCHF₂ 3-F F H A-1098. CHF₂ OCHF₂ 3-CH₃ F H A-1099. CHF₂ OCHF₂ 3-OCH₃ F HA-1100. CHF₂ OCHF₂ 5-F F H A-1101. CHF₂ OCHF₂ 5-CH₃ F H A-1102. CHF₂OCHF₂ 5-OCH₃ F H A-1103. CHF₂ OCF₃ 3-F F H A-1104. CHF₂ OCF₃ 3-CH₃ F HA-1105. CHF₂ OCF₃ 3-OCH₃ F H A-1106. CHF₂ OCF₃ 5-F F H A-1107. CHF₂ OCF₃5-CH₃ F H A-1108. CHF₂ OCF₃ 5-OCH₃ F H A-1109. CF₃ F 3-F F H A-1110. CF₃F 3-CH₃ F H A-1111. CF₃ F 3-OCH₃ F H A-1112. CF₃ F 5-F F H A-1113. CF₃ F5-CH₃ F H A-1114. CF₃ F 5-OCH₃ F H A-1115. CF₃ CH₃ 3-F F H A-1116. CF₃CH₃ 3-CH₃ F H A-1117. CF₃ CH₃ 3-OCH₃ F H A-1118. CF₃ CH₃ 5-F F H A-1119.CF₃ CH₃ 5-CH₃ F H A-1120. CF₃ CH₃ 5-OCH₃ F H A-1121. CF₃ OCH₃ 3-F F HA-1122. CF₃ OCH₃ 3-CH₃ F H A-1123. CF₃ OCH₃ 3-OCH₃ F H A-1124. CF₃ OCH₃5-F F H A-1125. CF₃ OCH₃ 5-CH₃ F H A-1126. CF₃ OCH₃ 5-OCH₃ F H A-1127.CF₃ CN 3-F F H A-1128. CF₃ CN 3-CH₃ F H A-1129. CF₃ CN 3-OCH₃ F HA-1130. CF₃ CN 5-F F H A-1131. CF₃ CN 5-CH₃ F H A-1132. CF₃ CN 5-OCH₃ FH A-1133. CF₃ CH₂F 3-F F H A-1134. CF₃ CH₂F 3-CH₃ F H A-1135. CF₃ CH₂F3-OCH₃ F H A-1136. CF₃ CH₂F 5-F F H A-1137. CF₃ CH₂F 5-CH₃ F H A-1138.CF₃ CH₂F 5-OCH₃ F H A-1139. CF₃ CHF₂ 3-F F H A-1140. CF₃ CHF₂ 3-CH₃ F HA-1141. CF₃ CHF₂ 3-OCH₃ F H A-1142. CF₃ CHF₂ 5-F F H A-1143. CF₃ CHF₂5-CH₃ F H A-1144. CF₃ CHF₂ 5-OCH₃ F H A-1145. CF₃ CF₃ 3-F F H A-1146.CF₃ CF₃ 3-CH₃ F H A-1147. CF₃ CF₃ 3-OCH₃ F H A-1148. CF₃ CF₃ 5-F F HA-1149. CF₃ CF₃ 5-CH₃ F H A-1150. CF₃ CF₃ 5-OCH₃ F H A-1151. CF₃ OCH₂F3-F F H A-1152. CF₃ OCH₂F 3-CH₃ F H A-1153. CF₃ OCH₂F 3-OCH₃ F H A-1154.CF₃ OCH₂F 5-F F H A-1155. CF₃ OCH₂F 5-CH₃ F H A-1156. CF₃ OCH₂F 5-OCH₃ FH A-1157. CF₃ OCHF₂ 3-F F H A-1158. CF₃ OCHF₂ 3-CH₃ F H A-1159. CF₃OCHF₂ 3-OCH₃ F H A-1160. CF₃ OCHF₂ 5-F F H A-1161. CF₃ OCHF₂ 5-CH₃ F HA-1162. CF₃ OCHF₂ 5-OCH₃ F H A-1163. CF₃ OCF₃ 3-F F H A-1164. CF₃ OCF₃3-CH₃ F H A-1165. CF₃ OCF₃ 3-OCH₃ F H A-1166. CF₃ OCF₃ 5-F F H A-1167.CF₃ OCF₃ 5-CH₃ F H A-1168. CF₃ OCF₃ 5-OCH₃ F H A-1169. OCH₂F F 3-F F HA-1170. OCH₂F F 3-CH₃ F H A-1171. OCH₂F F 3-OCH₃ F H A-1172. OCH₂F F 5-FF H A-1173. OCH₂F F 5-CH₃ F H A-1174. OCH₂F F 5-OCH₃ F H A-1175. OCH₂FCH₃ 3-F F H A-1176. OCH₂F CH₃ 3-CH₃ F H A-1177. OCH₂F CH₃ 3-OCH₃ F HA-1178. OCH₂F CH₃ 5-F F H A-1179. OCH₂F CH₃ 5-CH₃ F H A-1180. OCH₂F CH₃5-OCH₃ F H A-1181. OCH₂F OCH₃ 3-F F H A-1182. OCH₂F OCH₃ 3-CH₃ F HA-1183. OCH₂F OCH₃ 3-OCH₃ F H A-1184. OCH₂F OCH₃ 5-F F H A-1185. OCH₂FOCH₃ 5-CH₃ F H A-1186. OCH₂F OCH₃ 5-OCH₃ F H A-1187. OCH₂F CN 3-F F HA-1188. OCH₂F CN 3-CH₃ F H A-1189. OCH₂F CN 3-OCH₃ F H A-1190. OCH₂F CN5-F F H A-1191. OCH₂F CN 5-CH₃ F H A-1192. OCH₂F CN 5-OCH₃ F H A-1193.OCH₂F CH₂F 3-F F H A-1194. OCH₂F CH₂F 3-CH₃ F H A-1195. OCH₂F CH₂F3-OCH₃ F H A-1196. OCH₂F CH₂F 5-F F H A-1197. OCH₂F CH₂F 5-CH₃ F HA-1198. OCH₂F CH₂F 5-OCH₃ F H A-1199. OCH₂F CHF₂ 3-F F H A-1200. OCH₂FCHF₂ 3-CH₃ F H A-1201. OCH₂F CHF₂ 3-OCH₃ F H A-1202. OCH₂F CHF₂ 5-F F HA-1203. OCH₂F CHF₂ 5-CH₃ F H A-1204. OCH₂F CHF₂ 5-OCH₃ F H A-1205. OCH₂FCF₃ 3-F F H A-1206. OCH₂F CF₃ 3-CH₃ F H A-1207. OCH₂F CF₃ 3-OCH₃ F HA-1208. OCH₂F CF₃ 5-F F H A-1209. OCH₂F CF₃ 5-CH₃ F H A-1210. OCH₂F CF₃5-OCH₃ F H A-1211. OCH₂F OCH₂F 3-F F H A-1212. OCH₂F OCH₂F 3-CH₃ F HA-1213. OCH₂F OCH₂F 3-OCH₃ F H A-1214. OCH₂F OCH₂F 5-F F H A-1215. OCH₂FOCH₂F 5-CH₃ F H A-1216. OCH₂F OCH₂F 5-OCH₃ F H A-1217. OCH₂F OCHF₂ 3-F FH A-1218. OCH₂F OCHF₂ 3-CH₃ F H A-1219. OCH₂F OCHF₂ 3-OCH₃ F H A-1220.OCH₂F OCHF₂ 5-F F H A-1221. OCH₂F OCHF₂ 5-CH₃ F H A-1222. OCH₂F OCHF₂5-OCH₃ F H A-1223. OCH₂F OCF₃ 3-F F H A-1224. OCH₂F OCF₃ 3-CH₃ F HA-1225. OCH₂F OCF₃ 3-OCH₃ F H A-1226. OCH₂F OCF₃ 5-F F H A-1227. OCH₂FOCF₃ 5-CH₃ F H A-1228. OCH₂F OCF₃ 5-OCH₃ F H A-1229. OCHF₂ F 3-F F HA-1230. OCHF₂ F 3-CH₃ F H A-1231. OCHF₂ F 3-OCH₃ F H A-1232. OCHF₂ F 5-FF H A-1233. OCHF₂ F 5-CH₃ F H A-1234. OCHF₂ F 5-OCH₃ F H A-1235. OCHF₂CH₃ 3-F F H A-1236. OCHF₂ CH₃ 3-CH₃ F H A-1237. OCHF₂ CH₃ 3-OCH₃ F HA-1238. OCHF₂ CH₃ 5-F F H A-1239. OCHF₂ CH₃ 5-CH₃ F H A-1240. OCHF₂ CH₃5-OCH₃ F H A-1241. OCHF₂ OCH₃ 3-F F H A-1242. OCHF₂ OCH₃ 3-CH₃ F HA-1243. OCHF₂ OCH₃ 3-OCH₃ F H A-1244. OCHF₂ OCH₃ 5-F F H A-1245. OCHF₂OCH₃ 5-CH₃ F H A-1246. OCHF₂ OCH₃ 5-OCH₃ F H A-1247. OCHF₂ CN 3-F F HA-1248. OCHF₂ CN 3-CH₃ F H A-1249. OCHF₂ CN 3-OCH₃ F H A-1250. OCHF₂ CN5-F F H A-1251. OCHF₂ CN 5-CH₃ F H A-1252. OCHF₂ CN 5-OCH₃ F H A-1253.OCHF₂ CH₂F 3-F F H A-1254. OCHF₂ CH₂F 3-CH₃ F H A-1255. OCHF₂ CH₂F3-OCH₃ F H A-1256. OCHF₂ CH₂F 5-F F H A-1257. OCHF₂ CH₂F 5-CH₃ F HA-1258. OCHF₂ CH₂F 5-OCH₃ F H A-1259. OCHF₂ CHF₂ 3-F F H A-1260. OCHF₂CHF₂ 3-CH₃ F H A-1261. OCHF₂ CHF₂ 3-OCH₃ F H A-1262. OCHF₂ CHF₂ 5-F F HA-1263. OCHF₂ CHF₂ 5-CH₃ F H A-1264. OCHF₂ CHF₂ 5-OCH₃ F H A-1265. OCHF₂CF₃ 3-F F H A-1266. OCHF₂ CF₃ 3-CH₃ F H A-1267. OCHF₂ CF₃ 3-OCH₃ F HA-1268. OCHF₂ CF₃ 5-F F H A-1269. OCHF₂ CF₃ 5-CH₃ F H A-1270. OCHF₂ CF₃5-OCH₃ F H A-1271. OCHF₂ OCH₂F 3-F F H A-1272. OCHF₂ OCH₂F 3-CH₃ F HA-1273. OCHF₂ OCH₂F 3-OCH₃ F H A-1274. OCHF₂ OCH₂F 5-F F H A-1275. OCHF₂OCH₂F 5-CH₃ F H A-1276. OCHF₂ OCH₂F 5-OCH₃ F H A-1277. OCHF₂ OCHF₂ 3-F FH A-1278. OCHF₂ OCHF₂ 3-CH₃ F H A-1279. OCHF₂ OCHF₂ 3-OCH₃ F H A-1280.OCHF₂ OCHF₂ 5-F F H A-1281. OCHF₂ OCHF₂ 5-CH₃ F H A-1282. OCHF₂ OCHF₂5-OCH₃ F H A-1283. OCHF₂ OCF₃ 3-F F H A-1284. OCHF₂ OCF₃ 3-CH₃ F HA-1285. OCHF₂ OCF₃ 3-OCH₃ F H A-1286. OCHF₂ OCF₃ 5-F F H A-1287. OCHF₂OCF₃ 5-CH₃ F H A-1288. OCHF₂ OCF₃ 5-OCH₃ F H A-1289. OCF₃ F 3-F F HA-1290. OCF₃ F 3-CH₃ F H A-1291. OCF₃ F 3-OCH₃ F H A-1292. OCF₃ F 5-F FH A-1293. OCF₃ F 5-CH₃ F H A-1294. OCF₃ F 5-OCH₃ F H A-1295. OCF₃ CH₃3-F F H A-1296. OCF₃ CH₃ 3-CH₃ F H A-1297. OCF₃ CH₃ 3-OCH₃ F H A-1298.OCF₃ CH₃ 5-F F H A-1299. OCF₃ CH₃ 5-CH₃ F H A-1300. OCF₃ CH₃ 5-OCH₃ F HA-1301. OCF₃ OCH₃ 3-F F H A-1302. OCF₃ OCH₃ 3-CH₃ F H A-1303. OCF₃ OCH₃3-OCH₃ F H A-1304. OCF₃ OCH₃ 5-F F H A-1305. OCF₃ OCH₃ 5-CH₃ F H A-1306.OCF₃ OCH₃ 5-OCH₃ F H A-1307. OCF₃ CN 3-F F H A-1308. OCF₃ CN 3-CH₃ F HA-1309. OCF₃ CN 3-OCH₃ F H A-1310. OCF₃ CN 5-F F H A-1311. OCF₃ CN 5-CH₃F H A-1312. OCF₃ CN 5-OCH₃ F H A-1313. OCF₃ CH₂F 3-F F H A-1314. OCF₃CH₂F 3-CH₃ F H A-1315. OCF₃ CH₂F 3-OCH₃ F H A-1316. OCF₃ CH₂F 5-F F HA-1317. OCF₃ CH₂F 5-CH₃ F H A-1318. OCF₃ CH₂F 5-OCH₃ F H A-1319. OCF₃CHF₂ 3-F F H A-1320. OCF₃ CHF₂ 3-CH₃ F H A-1321. OCF₃ CHF₂ 3-OCH₃ F HA-1322. OCF₃ CHF₂ 5-F F H A-1323. OCF₃ CHF₂ 5-CH₃ F H A-1324. OCF₃ CHF₂5-OCH₃ F H A-1325. OCF₃ CF₃ 3-F F H A-1326. OCF₃ CF₃ 3-CH₃ F H A-1327.OCF₃ CF₃ 3-OCH₃ F H A-1328. OCF₃ CF₃ 5-F F H A-1329. OCF₃ CF₃ 5-CH₃ F HA-1330. OCF₃ CF₃ 5-OCH₃ F H A-1331. OCF₃ OCH₂F 3-F F H A-1332. OCF₃OCH₂F 3-CH₃ F H A-1333. OCF₃ OCH₂F 3-OCH₃ F H A-1334. OCF₃ OCH₂F 5-F F HA-1335. OCF₃ OCH₂F 5-CH₃ F H A-1336. OCF₃ OCH₂F 5-OCH₃ F H A-1337. OCF₃OCHF₂ 3-F F H A-1338. OCF₃ OCHF₂ 3-CH₃ F H A-1339. OCF₃ OCHF₂ 3-OCH₃ F HA-1340. OCF₃ OCHF₂ 5-F F H A-1341. OCF₃ OCHF₂ 5-CH₃ F H A-1342. OCF₃OCHF₂ 5-OCH₃ F H A-1343. OCF₃ OCF₃ 3-F F H A-1344. OCF₃ OCF₃ 3-CH₃ F HA-1345. OCF₃ OCF₃ 3-OCH₃ F H A-1346. OCF₃ OCF₃ 5-F F H A-1347. OCF₃ OCF₃5-CH₃ F H A-1348. OCF₃ OCF₃ 5-OCH₃ F H A-1349. H H H Cl H A-1350. F H HCl H A-1351. CH₃ H H Cl H A-1352. OCH₃ H H Cl H A-1353. CH₂F H H Cl HA-1354. CHF₂ H H Cl H A-1355. CF₃ H H Cl H A-1356. OCH₂F H H Cl HA-1357. OCHF₂ H H Cl H A-1358. OCF₃ H H Cl H A-1359. H F H Cl H A-1360.H CH₃ H Cl H A-1361. H OCH₃ H Cl H A-1362. H CN H Cl H A-1363. H CH₂F HCl H A-1364. H CHF₂ H Cl H A-1365. H CF₃ H Cl H A-1366. H OCH₂F H Cl HA-1367. H OCHF₂ H Cl H A-1368. H OCF₃ H Cl H A-1369. H H 3-F Cl HA-1370. H H 3-CH₃ Cl H A-1371. H H 3-OCH₃ Cl H A-1372. H H 5-F Cl HA-1373. H H 5-CH₃ Cl H A-1374. H H 5-OCH₃ Cl H A-1375. F F H Cl HA-1376. F CH₃ H Cl H A-1377. F OCH₃ H Cl H A-1378. F CN H Cl H A-1379. FCH₂F H Cl H A-1380. F CHF₂ H Cl H A-1381. F CF₃ H Cl H A-1382. F OCH₂F HCl H A-1383. F OCHF₂ H Cl H A-1384. F OCF₃ H Cl H A-1385. F H 3-F Cl HA-1386. F H 3-CH₃ Cl H A-1387. F H 3-OCH₃ Cl H A-1388. F H 5-F Cl HA-1389. F H 5-CH₃ Cl H A-1390. F H 5-OCH₃ Cl H A-1391. CH₃ F H Cl HA-1392. CH₃ CH₃ H Cl H A-1393. CH₃ OCH₃ H Cl H A-1394. CH₃ CN H Cl HA-1395. CH₃ CH₂F H Cl H A-1396. CH₃ CHF₂ H Cl H A-1397. CH₃ CF₃ H Cl HA-1398. CH₃ OCH₂F H Cl H A-1399. CH₃ OCHF₂ H Cl H A-1400. CH₃ OCF₃ H ClH A-1401. CH₃ H 3-F Cl H A-1402. CH₃ H 3-CH₃ Cl H A-1403. CH₃ H 3-OCH₃Cl H A-1404. CH₃ H 5-F Cl H A-1405. CH₃ H 5-CH₃ Cl H A-1406. CH₃ H5-OCH₃ Cl H A-1407. OCH₃ F H Cl H A-1408. OCH₃ CH₃ H Cl H A-1409. OCH₃OCH₃ H Cl H A-1410. OCH₃ CN H Cl H A-1411. OCH₃ CH₂F H Cl H A-1412. OCH₃CHF₂ H Cl H A-1413. OCH₃ CF₃ H Cl H A-1414. OCH₃ OCH₂F H Cl H A-1415.OCH₃ OCHF₂ H Cl H A-1416. OCH₃ OCF₃ H Cl H A-1417. OCH₃ H 3-F Cl HA-1418. OCH₃ H 3-CH₃ Cl H A-1419. OCH₃ H 3-OCH₃ Cl H A-1420. OCH₃ H 5-FCl H A-1421. OCH₃ H 5-CH₃ Cl H A-1422. OCH₃ H 5-OCH₃ Cl H A-1423. H F3-F Cl H A-1424. H F 3-CH₃ Cl H A-1425. H F 3-OCH₃ Cl H A-1426. H F 5-FCl H A-1427. H F 5-CH₃ Cl H A-1428. H F 5-OCH₃ Cl H A-1429. H CH₃ 3-F ClH A-1430. H CH₃ 3-CH₃ Cl H A-1431. H CH₃ 3-OCH₃ Cl H A-1432. H CH₃ 5-FCl H A-1433. H CH₃ 5-CH₃ Cl H A-1434. H CH₃ 5-OCH₃ Cl H A-1435. H OCH₃3-F Cl H A-1436. H OCH₃ 3-CH₃ Cl H A-1437. H OCH₃ 3-OCH₃ Cl H A-1438. HOCH₃ 5-F Cl H A-1439. H OCH₃ 5-CH₃ Cl H A-1440. H OCH₃ 5-OCH₃ Cl HA-1441. H CN 3-F Cl H A-1442. H CN 3-CH₃ Cl H A-1443. H CN 3-OCH₃ Cl HA-1444. H CN 5-F Cl H A-1445. H CN 5-CH₃ Cl H A-1446. H CN 5-OCH₃ Cl HA-1447. H CH₂F 3-F Cl H A-1448. H CH₂F 3-CH₃ Cl H A-1449. H CH₂F 3-OCH₃Cl H A-1450. H CH₂F 5-F Cl H A-1451. H CH₂F 5-CH₃ Cl H A-1452. H CH₂F5-OCH₃ Cl H A-1453. H CHF₂ 3-F Cl H A-1454. H CHF₂ 3-CH₃ Cl H A-1455. HCHF₂ 3-OCH₃ Cl H A-1456. H CHF₂ 5-F Cl H A-1457. H CHF₂ 5-CH₃ Cl HA-1458. H CHF₂ 5-OCH₃ Cl H A-1459. H CF₃ 3-F Cl H A-1460. H CF₃ 3-CH₃ ClH A-1461. H CF₃ 3-OCH₃ Cl H A-1462. H CF₃ 5-F Cl H A-1463. H CF₃ 5-CH₃Cl H A-1464. H CF₃ 5-OCH₃ Cl H A-1465. H OCH₂F 3-F Cl H A-1466. H OCH₂F3-CH₃ Cl H A-1467. H OCH₂F 3-OCH₃ Cl H A-1468. H OCH₂F 5-F Cl H A-1469.H OCH₂F 5-CH₃ Cl H A-1470. H OCH₂F 5-OCH₃ Cl H A-1471. H OCHF₂ 3-F Cl HA-1472. H OCHF₂ 3-CH₃ Cl H A-1473. H OCHF₂ 3-OCH₃ Cl H A-1474. H OCHF₂5-F Cl H A-1475. H OCHF₂ 5-CH₃ Cl H A-1476. H OCHF₂ 5-OCH₃ Cl H A-1477.H OCF₃ 3-F Cl H A-1478. H OCF₃ 3-CH₃ Cl H A-1479. H OCF₃ 3-OCH₃ Cl HA-1480. H OCF₃ 5-F Cl H A-1481. H OCF₃ 5-CH₃ Cl H A-1482. H OCF₃ 5-OCH₃Cl H A-1483. F F 3-F Cl H A-1484. F F 3-CH₃ Cl H A-1485. F F 3-OCH₃ Cl HA-1486. F F 5-F Cl H A-1487. F F 5-CH₃ Cl H A-1488. F F 5-OCH₃ Cl HA-1489. F CH₃ 3-F Cl H A-1490. F CH₃ 3-CH₃ Cl H A-1491. F CH₃ 3-OCH₃ ClH A-1492. F CH₃ 5-F Cl H A-1493. F CH₃ 5-CH₃ Cl H A-1494. F CH₃ 5-OCH₃Cl H A-1495. F OCH₃ 3-F Cl H A-1496. F OCH₃ 3-CH₃ Cl H A-1497. F OCH₃3-OCH₃ Cl H A-1498. F OCH₃ 5-F Cl H A-1499. F OCH₃ 5-CH₃ Cl H A-1500. FOCH₃ 5-OCH₃ Cl H A-1501. F CN 3-F Cl H A-1502. F CN 3-CH₃ Cl H A-1503. FCN 3-OCH₃ Cl H A-1504. F CN 5-F Cl H A-1505. F CN 5-CH₃ Cl H A-1506. FCN 5-OCH₃ Cl H A-1507. F CH₂F 3-F Cl H A-1508. F CH₂F 3-CH₃ Cl H A-1509.F CH₂F 3-OCH₃ Cl H A-1510. F CH₂F 5-F Cl H A-1511. F CH₂F 5-CH₃ Cl HA-1512. F CH₂F 5-OCH₃ Cl H A-1513. F CHF₂ 3-F Cl H A-1514. F CHF₂ 3-CH₃Cl H A-1515. F CHF₂ 3-OCH₃ Cl H A-1516. F CHF₂ 5-F Cl H A-1517. F CHF₂5-CH₃ Cl H A-1518. F CHF₂ 5-OCH₃ Cl H A-2807. H CF₃ 3-F F F A-2808. HCF₃ 3-CH₃ F F A-2809. H CF₃ 3-OCH₃ F F A-2810. H CF₃ 5-F F F A-2811. HCF₃ 5-CH₃ F F A-2812. H CF₃ 5-OCH₃ F F A-2813. H OCH₂F 3-F F F A-2814. HOCH₂F 3-CH₃ F F A-2815. H OCH₂F 3-OCH₃ F F A-2816. H OCH₂F 5-F F FA-2817. H OCH₂F 5-CH₃ F F A-2818. H OCH₂F 5-OCH₃ F F A-2819. H OCHF₂ 3-FF F A-2820. H OCHF₂ 3-CH₃ F F A-2821. H OCHF₂ 3-OCH₃ F F A-2822. H OCHF₂5-F F F A-2823. H OCHF₂ 5-CH₃ F F A-2824. H OCHF₂ 5-OCH₃ F F A-2825. HOCF₃ 3-F F F A-2826. H OCF₃ 3-CH₃ F F A-2827. H OCF₃ 3-OCH₃ F F A-2828.H OCF₃ 5-F F F A-2829. H OCF₃ 5-CH₃ F F A-2830. H OCF₃ 5-OCH₃ F FA-2831. F F 3-F F F A-2832. F F 3-CH₃ F F A-2833. F F 3-OCH₃ F F A-2834.F F 5-F F F A-2835. F F 5-CH₃ F F A-2836. F F 5-OCH₃ F F A-2837. F CH₃3-F F F A-2838. F CH₃ 3-CH₃ F F A-2839. F CH₃ 3-OCH₃ F F A-2840. F CH₃5-F F F A-2841. F CH₃ 5-CH₃ F F A-2842. F CH₃ 5-OCH₃ F F A-2843. F OCH₃3-F F F A-2844. F OCH₃ 3-CH₃ F F A-2845. F OCH₃ 3-OCH₃ F F A-2846. FOCH₃ 5-F F F A-2847. F OCH₃ 5-CH₃ F F A-2848. F OCH₃ 5-OCH₃ F F A-2849.F CN 3-F F F A-2850. F CN 3-CH₃ F F A-2851. F CN 3-OCH₃ F F A-2852. F CN5-F F F A-2853. F CN 5-CH₃ F F A-2854. F CN 5-OCH₃ F F A-2855. F CH₂F3-F F F A-2856. F CH₂F 3-CH₃ F F A-2857. F CH₂F 3-OCH₃ F F A-2858. FCH₂F 5-F F F A-2859. F CH₂F 5-CH₃ F F A-2860. F CH₂F 5-OCH₃ F F A-2861.F CHF₂ 3-F F F A-2862. F CHF₂ 3-CH₃ F F A-2863. F CHF₂ 3-OCH₃ F FA-2864. F CHF₂ 5-F F F A-2865. F CHF₂ 5-CH₃ F F A-2866. F CHF₂ 5-OCH₃ FF A-2867. F CF₃ 3-F F F A-2868. F CF₃ 3-CH₃ F F A-2869. F CF₃ 3-OCH₃ F FA-2870. F CF₃ 5-F F F A-2871. F CF₃ 5-CH₃ F F A-2872. F CF₃ 5-OCH₃ F FA-2873. F OCH₂F 3-F F F A-2874. F OCH₂F 3-CH₃ F F A-2875. F OCH₂F 3-OCH₃F F A-2876. F OCH₂F 5-F F F A-2877. F OCH₂F 5-CH₃ F F A-2878. F OCH₂F5-OCH₃ F F A-2879. F OCHF₂ 3-F F F A-2880. F OCHF₂ 3-CH₃ F F A-2881. FOCHF₂ 3-OCH₃ F F A-2882. F OCHF₂ 5-F F F A-2883. F OCHF₂ 5-CH₃ F FA-2884. F OCHF₂ 5-OCH₃ F F A-2885. F OCF₃ 3-F F F A-2886. F OCF₃ 3-CH₃ FF A-2887. F OCF₃ 3-OCH₃ F F A-2888. F OCF₃ 5-F F F A-2889. F OCF₃ 5-CH₃F F A-2890. F OCF₃ 5-OCH₃ F F A-2891. CH₃ F 3-F F F A-2892. CH₃ F 3-CH₃F F A-2893. CH₃ F 3-OCH₃ F F A-2894. CH₃ F 5-F F F A-2895. CH₃ F 5-CH₃ FF A-2896. CH₃ F 5-OCH₃ F F A-2897. CH₃ CH₃ 3-F F F A-2898. CH₃ CH₃ 3-CH₃F F A-2899. CH₃ CH₃ 3-OCH₃ F F A-2900. CH₃ CH₃ 5-F F F A-2901. CH₃ CH₃5-CH₃ F F A-2902. CH₃ CH₃ 5-OCH₃ F F A-2903. CH₃ OCH₃ 3-F F F A-2904.CH₃ OCH₃ 3-CH₃ F F A-2905. CH₃ OCH₃ 3-OCH₃ F F A-2906. CH₃ OCH₃ 5-F F FA-2907. CH₃ OCH₃ 5-CH₃ F F A-2908. CH₃ OCH₃ 5-OCH₃ F F A-2909. CH₃ CN3-F F F A-2910. CH₃ CN 3-CH₃ F F A-2911. CH₃ CN 3-OCH₃ F F A-2912. CH₃CN 5-F F F A-2913. CH₃ CN 5-CH₃ F F A-2914. CH₃ CN 5-OCH₃ F F A-2915.CH₃ CH₂F 3-F F F A-2916. CH₃ CH₂F 3-CH₃ F F A-2917. CH₃ CH₂F 3-OCH₃ F FA-2918. CH₃ CH₂F 5-F F F A-2919. CH₃ CH₂F 5-CH₃ F F A-2920. CH₃ CH₂F5-OCH₃ F F A-2921. CH₃ CHF₂ 3-F F F A-2922. CH₃ CHF₂ 3-CH₃ F F A-2923.CH₃ CHF₂ 3-OCH₃ F F A-2924. CH₃ CHF₂ 5-F F F A-2925. CH₃ CHF₂ 5-CH₃ F FA-2926. CH₃ CHF₂ 5-OCH₃ F F A-2927. CH₃ CF₃ 3-F F F A-2928. CH₃ CF₃3-CH₃ F F A-2929. CH₃ CF₃ 3-OCH₃ F F A-2930. CH₃ CF₃ 5-F F F A-2931. CH₃CF₃ 5-CH₃ F F A-2932. CH₃ CF₃ 5-OCH₃ F F A-2933. CH₃ OCH₂F 3-F F FA-2934. CH₃ OCH₂F 3-CH₃ F F A-2935. CH₃ OCH₂F 3-OCH₃ F F A-2936. CH₃OCH₂F 5-F F F A-2937. CH₃ OCH₂F 5-CH₃ F F A-2938. CH₃ OCH₂F 5-OCH₃ F FA-2939. CH₃ OCHF₂ 3-F F F A-2940. CH₃ OCHF₂ 3-CH₃ F F A-2941. CH₃ OCHF₂3-OCH₃ F F A-2942. CH₃ OCHF₂ 5-F F F A-2943. CH₃ OCHF₂ 5-CH₃ F F A-2944.CH₃ OCHF₂ 5-OCH₃ F F A-2945. CH₃ OCF₃ 3-F F F A-2946. CH₃ OCF₃ 3-CH₃ F FA-2947. CH₃ OCF₃ 3-OCH₃ F F A-2948. CH₃ OCF₃ 5-F F F A-2949. CH₃ OCF₃5-CH₃ F F A-2950. CH₃ OCF₃ 5-OCH₃ F F A-2951. OCH₃ F 3-F F F A-2952.OCH₃ F 3-CH₃ F F A-2953. OCH₃ F 3-OCH₃ F F A-2954. OCH₃ F 5-F F FA-2955. OCH₃ F 5-CH₃ F F A-2956. OCH₃ F 5-OCH₃ F F A-2957. OCH₃ CH₃ 3-FF F A-2958. OCH₃ CH₃ 3-CH₃ F F A-2959. OCH₃ CH₃ 3-OCH₃ F F A-2960. OCH₃CH₃ 5-F F F A-2961. OCH₃ CH₃ 5-CH₃ F F A-2962. OCH₃ CH₃ 5-OCH₃ F FA-2963. OCH₃ OCH₃ 3-F F F A-2964. OCH₃ OCH₃ 3-CH₃ F F A-2965. OCH₃ OCH₃3-OCH₃ F F A-2966. OCH₃ OCH₃ 5-F F F A-2967. OCH₃ OCH₃ 5-CH₃ F F A-2968.OCH₃ OCH₃ 5-OCH₃ F F A-2969. OCH₃ CN 3-F F F A-2970. OCH₃ CN 3-CH₃ F FA-2971. OCH₃ CN 3-OCH₃ F F A-2972. OCH₃ CN 5-F F F A-2973. OCH₃ CN 5-CH₃F F A-2974. OCH₃ CN 5-OCH₃ F F A-2975. OCH₃ CH₂F 3-F F F A-2976. OCH₃CH₂F 3-CH₃ F F A-2977. OCH₃ CH₂F 3-OCH₃ F F A-2978. OCH₃ CH₂F 5-F F FA-2979. OCH₃ CH₂F 5-CH₃ F F A-2980. OCH₃ CH₂F 5-OCH₃ F F A-2981. OCH₃CHF₂ 3-F F F A-2982. OCH₃ CHF₂ 3-CH₃ F F A-2983. OCH₃ CHF₂ 3-OCH₃ F FA-2984. OCH₃ CHF₂ 5-F F F A-2985. OCH₃ CHF₂ 5-CH₃ F F A-2986. OCH₃ CHF₂5-OCH₃ F F A-2987. OCH₃ CF₃ 3-F F F A-2988. OCH₃ CF₃ 3-CH₃ F F A-2989.OCH₃ CF₃ 3-OCH₃ F F A-2990. OCH₃ CF₃ 5-F F F A-2991. OCH₃ CF₃ 5-CH₃ F FA-2992. OCH₃ CF₃ 5-OCH₃ F F A-2993. OCH₃ OCH₂F 3-F F F A-2994. OCH₃OCH₂F 3-CH₃ F F A-2995. OCH₃ OCH₂F 3-OCH₃ F F A-2996. OCH₃ OCH₂F 5-F F FA-2997. OCH₃ OCH₂F 5-CH₃ F F A-2998. OCH₃ OCH₂F 5-OCH₃ F F A-2999. OCH₃OCHF₂ 3-F F F A-3000. OCH₃ OCHF₂ 3-CH₃ F F A-3001. OCH₃ OCHF₂ 3-OCH₃ F FA-3002. OCH₃ OCHF₂ 5-F F F A-3003. OCH₃ OCHF₂ 5-CH₃ F F A-3004. OCH₃OCHF₂ 5-OCH₃ F F A-3005. OCH₃ OCF₃ 3-F F F A-3006. OCH₃ OCF₃ 3-CH₃ F FA-3007. OCH₃ OCF₃ 3-OCH₃ F F A-3008. OCH₃ OCF₃ 5-F F F A-3009. OCH₃ OCF₃5-CH₃ F F A-3010. OCH₃ OCF₃ 5-OCH₃ F F A-3011. CH₂F F 3-F F F A-3012.CH₂F F 3-CH₃ F F A-3013. CH₂F F 3-OCH₃ F F A-3014. CH₂F F 5-F F FA-3015. CH₂F F 5-CH₃ F F A-3016. CH₂F F 5-OCH₃ F F A-3017. CH₂F CH₃ 3-FF F A-3018. CH₂F CH₃ 3-CH₃ F F A-3019. CH₂F CH₃ 3-OCH₃ F F A-3020. CH₂FCH₃ 5-F F F A-3021. CH₂F CH₃ 5-CH₃ F F A-3022. CH₂F CH₃ 5-OCH₃ F FA-3023. CH₂F OCH₃ 3-F F F A-3024. CH₂F OCH₃ 3-CH₃ F F A-3025. CH₂F OCH₃3-OCH₃ F F A-3026. CH₂F OCH₃ 5-F F F A-3027. CH₂F OCH₃ 5-CH₃ F F A-3028.CH₂F OCH₃ 5-OCH₃ F F A-3029. CH₂F CN 3-F F F A-3030. CH₂F CN 3-CH₃ F FA-3031. CH₂F CN 3-OCH₃ F F A-3032. CH₂F CN 5-F F F A-3033. CH₂F CN 5-CH₃F F A-3034. CH₂F CN 5-OCH₃ F F A-3035. CH₂F CH₂F 3-F F F A-3036. CH₂FCH₂F 3-CH₃ F F A-3037. CH₂F CH₂F 3-OCH₃ F F A-3038. CH₂F CH₂F 5-F F FA-3039. CH₂F CH₂F 5-CH₃ F F A-3040. CH₂F CH₂F 5-OCH₃ F F A-3041. CH₂FCHF₂ 3-F F F A-3042. CH₂F CHF₂ 3-CH₃ F F A-3043. CH₂F CHF₂ 3-OCH₃ F FA-3044. CH₂F CHF₂ 5-F F F A-3045. CH₂F CHF₂ 5-CH₃ F F A-3046. CH₂F CHF₂5-OCH₃ F F A-3047. CH₂F CF₃ 3-F F F A-3048. CH₂F CF₃ 3-CH₃ F F A-3049.CH₂F CF₃ 3-OCH₃ F F A-3050. CH₂F CF₃ 5-F F F A-3051. CH₂F CF₃ 5-CH₃ F FA-3052. CH₂F CF₃ 5-OCH₃ F F A-3053. CH₂F OCH₂F 3-F F F A-3054. CH₂FOCH₂F 3-CH₃ F F A-3055. CH₂F OCH₂F 3-OCH₃ F F A-3056. CH₂F OCH₂F 5-F F FA-3057. CH₂F OCH₂F 5-CH₃ F F A-3058. CH₂F OCH₂F 5-OCH₃ F F A-3059. CH₂FOCHF₂ 3-F F F A-3060. CH₂F OCHF₂ 3-CH₃ F F A-3061. CH₂F OCHF₂ 3-OCH₃ F FA-3062. CH₂F OCHF₂ 5-F F F A-3063. CH₂F OCHF₂ 5-CH₃ F F A-3064. CH₂FOCHF₂ 5-OCH₃ F F A-3065. CH₂F OCF₃ 3-F F F A-3066. CH₂F OCF₃ 3-CH₃ F FA-3067. CH₂F OCF₃ 3-OCH₃ F F A-3068. CH₂F OCF₃ 5-F F F A-3069. CH₂F OCF₃5-CH₃ F F A-3070. CH₂F OCF₃ 5-OCH₃ F F A-3071. CHF₂ F 3-F F F A-3072.CHF₂ F 3-CH₃ F F A-3073. CHF₂ F 3-OCH₃ F F A-3074. CHF₂ F 5-F F FA-3075. CHF₂ F 5-CH₃ F F A-3076. CHF₂ F 5-OCH₃ F F A-3077. CHF₂ CH₃ 3-FF F A-3078. CHF₂ CH₃ 3-CH₃ F F A-3079. CHF₂ CH₃ 3-OCH₃ F F A-3080. CHF₂CH₃ 5-F F F A-3081. CHF₂ CH₃ 5-CH₃ F F A-3082. CHF₂ CH₃ 5-OCH₃ F FA-3083. CHF₂ OCH₃ 3-F F F A-3084. CHF₂ OCH₃ 3-CH₃ F F A-3085. CHF₂ OCH₃3-OCH₃ F F A-3086. CHF₂ OCH₃ 5-F F F A-3087. CHF₂ OCH₃ 5-CH₃ F F A-3088.CHF₂ OCH₃ 5-OCH₃ F F A-3089. CHF₂ CN 3-F F F A-3090. CHF₂ CN 3-CH₃ F FA-3091. CHF₂ CN 3-OCH₃ F F A-3092. CHF₂ CN 5-F F F A-3093. CHF₂ CN 5-CH₃F F A-3094. CHF₂ CN 5-OCH₃ F F A-3095. CHF₂ CH₂F 3-F F F A-3096. CHF₂CH₂F 3-CH₃ F F A-3097. CHF₂ CH₂F 3-OCH₃ F F A-3098. CHF₂ CH₂F 5-F F FA-3099. CHF₂ CH₂F 5-CH₃ F F A-3100. CHF₂ CH₂F 5-OCH₃ F F A-3101. CHF₂CHF₂ 3-F F F A-3102. CHF₂ CHF₂ 3-CH₃ F F A-3103. CHF₂ CHF₂ 3-OCH₃ F FA-3104. CHF₂ CHF₂ 5-F F F A-3105. CHF₂ CHF₂ 5-CH₃ F F A-3106. CHF₂ CHF₂5-OCH₃ F F A-3107. CHF₂ CF₃ 3-F F F A-3108. CHF₂ CF₃ 3-CH₃ F F A-3109.CHF₂ CF₃ 3-OCH₃ F F A-3110. CHF₂ CF₃ 5-F F F A-3111. CHF₂ CF₃ 5-CH₃ F FA-3112. CHF₂ CF₃ 5-OCH₃ F F A-3113. CHF₂ OCH₂F 3-F F F A-3114. CHF₂OCH₂F 3-CH₃ F F A-3115. CHF₂ OCH₂F 3-OCH₃ F F A-3116. CHF₂ OCH₂F 5-F F FA-3117. CHF₂ OCH₂F 5-CH₃ F F A-3118. CHF₂ OCH₂F 5-OCH₃ F F A-3119. CHF₂OCHF₂ 3-F F F A-3120. CHF₂ OCHF₂ 3-CH₃ F F A-3121. CHF₂ OCHF₂ 3-OCH₃ F FA-3122. CHF₂ OCHF₂ 5-F F F A-3123. CHF₂ OCHF₂ 5-CH₃ F F A-3124. CHF₂OCHF₂ 5-OCH₃ F F A-3125. CHF₂ OCF₃ 3-F F F A-3126. CHF₂ OCF₃ 3-CH₃ F FA-3127. CHF₂ OCF₃ 3-OCH₃ F F A-3128. CHF₂ OCF₃ 5-F F F A-3129. CHF₂ OCF₃5-CH₃ F F A-3130. CHF₂ OCF₃ 5-OCH₃ F F A-3131. CF₃ F 3-F F F A-3132. CF₃F 3-CH₃ F F A-3133. CF₃ F 3-OCH₃ F F A-3134. CF₃ F 5-F F F A-3135. CF₃ F5-CH₃ F F A-3136. CF₃ F 5-OCH₃ F F A-3137. CF₃ CH₃ 3-F F F A-3138. CF₃CH₃ 3-CH₃ F F A-3139. CF₃ CH₃ 3-OCH₃ F F A-3140. CF₃ CH₃ 5-F F F A-3141.CF₃ CH₃ 5-CH₃ F F A-3142. CF₃ CH₃ 5-OCH₃ F F A-3143. CF₃ OCH₃ 3-F F FA-3144. CF₃ OCH₃ 3-CH₃ F F A-3145. CF₃ OCH₃ 3-OCH₃ F F A-3146. CF₃ OCH₃5-F F F A-3147. CF₃ OCH₃ 5-CH₃ F F A-3148. CF₃ OCH₃ 5-OCH₃ F F A-3149.CF₃ CN 3-F F F A-3150. CF₃ CN 3-CH₃ F F A-3151. CF₃ CN 3-OCH₃ F FA-3152. CF₃ CN 5-F F F A-3153. CF₃ CN 5-CH₃ F F A-3154. CF₃ CN 5-OCH₃ FF A-3155. CF₃ CH₂F 3-F F F A-3156. CF₃ CH₂F 3-CH₃ F F A-3157. CF₃ CH₂F3-OCH₃ F F A-3158. CF₃ CH₂F 5-F F F A-3159. CF₃ CH₂F 5-CH₃ F F A-3160.CF₃ CH₂F 5-OCH₃ F F A-3161. CF₃ CHF₂ 3-F F F A-3162. CF₃ CHF₂ 3-CH₃ F FA-3163. CF₃ CHF₂ 3-OCH₃ F F A-3164. CF₃ CHF₂ 5-F F F A-3165. CF₃ CHF₂5-CH₃ F F A-3166. CF₃ CHF₂ 5-OCH₃ F F A-3167. CF₃ CF₃ 3-F F F A-3168.CF₃ CF₃ 3-CH₃ F F A-3169. CF₃ CF₃ 3-OCH₃ F F A-3170. CF₃ CF₃ 5-F F FA-3171. CF₃ CF₃ 5-CH₃ F F A-3172. CF₃ CF₃ 5-OCH₃ F F A-3173. CF₃ OCH₂F3-F F F A-3174. CF₃ OCH₂F 3-CH₃ F F A-3175. CF₃ OCH₂F 3-OCH₃ F F A-3176.CF₃ OCH₂F 5-F F F A-3177. CF₃ OCH₂F 5-CH₃ F F A-3178. CF₃ OCH₂F 5-OCH₃ FF A-3179. CF₃ OCHF₂ 3-F F F A-3180. CF₃ OCHF₂ 3-CH₃ F F A-3181. CF₃OCHF₂ 3-OCH₃ F F A-3182. CF₃ OCHF₂ 5-F F F A-3183. CF₃ OCHF₂ 5-CH₃ F FA-3184. CF₃ OCHF₂ 5-OCH₃ F F A-3185. CF₃ OCF₃ 3-F F F A-3186. CF₃ OCF₃3-CH₃ F F A-3187. CF₃ OCF₃ 3-OCH₃ F F A-3188. CF₃ OCF₃ 5-F F F A-3189.CF₃ OCF₃ 5-CH₃ F F A-3190. CF₃ OCF₃ 5-OCH₃ F F A-3191. OCH₂F F 3-F F FA-3192. OCH₂F F 3-CH₃ F F A-3193. OCH₂F F 3-OCH₃ F F A-3194. OCH₂F F 5-FF F A-3195. OCH₂F F 5-CH₃ F F A-3196. OCH₂F F 5-OCH₃ F F A-3197. OCH₂FCH₃ 3-F F F A-3198. OCH₂F CH₃ 3-CH₃ F F A-3199. OCH₂F CH₃ 3-OCH₃ F FA-3200. OCH₂F CH₃ 5-F F F A-3201. OCH₂F CH₃ 5-CH₃ F F A-3202. OCH₂F CH₃5-OCH₃ F F A-3203. OCH₂F OCH₃ 3-F F F A-3204. OCH₂F OCH₃ 3-CH₃ F FA-3205. OCH₂F OCH₃ 3-OCH₃ F F A-3206. OCH₂F OCH₃ 5-F F F A-3207. OCH₂FOCH₃ 5-CH₃ F F A-3208. OCH₂F OCH₃ 5-OCH₃ F F A-3209. OCH₂F CN 3-F F FA-3210. OCH₂F CN 3-CH₃ F F A-3211. OCH₂F CN 3-OCH₃ F F A-3212. OCH₂F CN5-F F F A-3213. OCH₂F CN 5-CH₃ F F A-3214. OCH₂F CN 5-OCH₃ F F A-3215.OCH₂F CH₂F 3-F F F A-3216. OCH₂F CH₂F 3-CH₃ F F A-3217. OCH₂F CH₂F3-OCH₃ F F A-3218. OCH₂F CH₂F 5-F F F A-3219. OCH₂F CH₂F 5-CH₃ F FA-3220. OCH₂F CH₂F 5-OCH₃ F F A-3221. OCH₂F CHF₂ 3-F F F A-3222. OCH₂FCHF₂ 3-CH₃ F F A-3223. OCH₂F CHF₂ 3-OCH₃ F F A-3224. OCH₂F CHF₂ 5-F F FA-3225. OCH₂F CHF₂ 5-CH₃ F F A-3226. OCH₂F CHF₂ 5-OCH₃ F F A-3227. OCH₂FCF₃ 3-F F F A-3228. OCH₂F CF₃ 3-CH₃ F F A-3229. OCH₂F CF₃ 3-OCH₃ F FA-3230. OCH₂F CF₃ 5-F F F A-3231. OCH₂F CF₃ 5-CH₃ F F A-3232. OCH₂F CF₃5-OCH₃ F F A-3233. OCH₂F OCH₂F 3-F F F A-3234. OCH₂F OCH₂F 3-CH₃ F FA-3235. OCH₂F OCH₂F 3-OCH₃ F F A-3236. OCH₂F OCH₂F 5-F F F A-3237. OCH₂FOCH₂F 5-CH₃ F F A-3238. OCH₂F OCH₂F 5-OCH₃ F F A-3239. OCH₂F OCHF₂ 3-F FF A-3240. OCH₂F OCHF₂ 3-CH₃ F F A-3241. OCH₂F OCHF₂ 3-OCH₃ F F A-3242.OCH₂F OCHF₂ 5-F F F A-3243. OCH₂F OCHF₂ 5-CH₃ F F A-3244. OCH₂F OCHF₂5-OCH₃ F F A-3245. OCH₂F OCF₃ 3-F F F A-3246. OCH₂F OCF₃ 3-CH₃ F FA-3247. OCH₂F OCF₃ 3-OCH₃ F F A-3248. OCH₂F OCF₃ 5-F F F A-3249. OCH₂FOCF₃ 5-CH₃ F F A-3250. OCH₂F OCF₃ 5-OCH₃ F F A-3251. OCHF₂ F 3-F F FA-3252. OCHF₂ F 3-CH₃ F F A-3253. OCHF₂ F 3-OCH₃ F F A-3254. OCHF₂ F 5-FF F A-3255. OCHF₂ F 5-CH₃ F F A-3256. OCHF₂ F 5-OCH₃ F F A-3257. OCHF₂CH₃ 3-F F F A-3258. OCHF₂ CH₃ 3-CH₃ F F A-3259. OCHF₂ CH₃ 3-OCH₃ F FA-3260. OCHF₂ CH₃ 5-F F F A-3261. OCHF₂ CH₃ 5-CH₃ F F A-3262. OCHF₂ CH₃5-OCH₃ F F A-3263. OCHF₂ OCH₃ 3-F F F A-3264. OCHF₂ OCH₃ 3-CH₃ F FA-3265. OCHF₂ OCH₃ 3-OCH₃ F F A-3266. OCHF₂ OCH₃ 5-F F F A-3267. OCHF₂OCH₃ 5-CH₃ F F A-3268. OCHF₂ OCH₃ 5-OCH₃ F F A-3269. OCHF₂ CN 3-F F FA-3270. OCHF₂ CN 3-CH₃ F F A-3271. OCHF₂ CN 3-OCH₃ F F A-3272. OCHF₂ CN5-F F F A-3273. OCHF₂ CN 5-CH₃ F F A-3274. OCHF₂ CN 5-OCH₃ F F A-3275.OCHF₂ CH₂F 3-F F F A-3276. OCHF₂ CH₂F 3-CH₃ F F A-3277. OCHF₂ CH₂F3-OCH₃ F F A-3278. OCHF₂ CH₂F 5-F F F A-3279. OCHF₂ CH₂F 5-CH₃ F FA-3280. OCHF₂ CH₂F 5-OCH₃ F F A-3281. OCHF₂ CHF₂ 3-F F F A-3282. OCHF₂CHF₂ 3-CH₃ F F A-3283. OCHF₂ CHF₂ 3-OCH₃ F F A-3284. OCHF₂ CHF₂ 5-F F FA-3285. OCHF₂ CHF₂ 5-CH₃ F F A-3286. OCHF₂ CHF₂ 5-OCH₃ F F A-3287. OCHF₂CF₃ 3-F F F A-3288. OCHF₂ CF₃ 3-CH₃ F F A-3289. OCHF₂ CF₃ 3-OCH₃ F FA-3290. OCHF₂ CF₃ 5-F F F A-3291. OCHF₂ CF₃ 5-CH₃ F F A-3292. OCHF₂ CF₃5-OCH₃ F F A-3293. OCHF₂ OCH₂F 3-F F F A-3294. OCHF₂ OCH₂F 3-CH₃ F FA-3295. OCHF₂ OCH₂F 3-OCH₃ F F A-3296. OCHF₂ OCH₂F 5-F F F A-3297. OCHF₂OCH₂F 5-CH₃ F F A-3298. OCHF₂ OCH₂F 5-OCH₃ F F A-3299. OCHF₂ OCHF₂ 3-F FF A-3300. OCHF₂ OCHF₂ 3-CH₃ F F A-3301. OCHF₂ OCHF₂ 3-OCH₃ F F A-3302.OCHF₂ OCHF₂ 5-F F F A-3303. OCHF₂ OCHF₂ 5-CH₃ F F A-3304. OCHF₂ OCHF₂5-OCH₃ F F A-3305. OCHF₂ OCF₃ 3-F F F A-3306. OCHF₂ OCF₃ 3-CH₃ F FA-3307. OCHF₂ OCF₃ 3-OCH₃ F F A-3308. OCHF₂ OCF₃ 5-F F F A-3309. OCHF₂OCF₃ 5-CH₃ F F A-3310. OCHF₂ OCF₃ 5-OCH₃ F F A-3311. OCF₃ F 3-F F FA-3312. OCF₃ F 3-CH₃ F F A-3313. OCF₃ F 3-OCH₃ F F A-3314. OCF₃ F 5-F FF A-3315. OCF₃ F 5-CH₃ F F A-3316. OCF₃ F 5-OCH₃ F F A-3317. OCF₃ CH₃3-F F F A-3318. OCF₃ CH₃ 3-CH₃ F F A-3319. OCF₃ CH₃ 3-OCH₃ F F A-3320.OCF₃ CH₃ 5-F F F A-3321. OCF₃ CH₃ 5-CH₃ F F A-3322. OCF₃ CH₃ 5-OCH₃ F FA-3323. OCF₃ OCH₃ 3-F F F A-3324. OCF₃ OCH₃ 3-CH₃ F F A-3325. OCF₃ OCH₃3-OCH₃ F F A-3326. OCF₃ OCH₃ 5-F F F A-3327. OCF₃ OCH₃ 5-CH₃ F F A-3328.OCF₃ OCH₃ 5-OCH₃ F F A-3329. OCF₃ CN 3-F F F A-3330. OCF₃ CN 3-CH₃ F FA-3331. OCF₃ CN 3-OCH₃ F F A-3332. OCF₃ CN 5-F F F A-3333. OCF₃ CN 5-CH₃F F A-3334. OCF₃ CN 5-OCH₃ F F A-3335. OCF₃ CH₂F 3-F F F A-3336. OCF₃CH₂F 3-CH₃ F F A-3337. OCF₃ CH₂F 3-OCH₃ F F A-3338. OCF₃ CH₂F 5-F F FA-3339. OCF₃ CH₂F 5-CH₃ F F A-3340. OCF₃ CH₂F 5-OCH₃ F F A-3341. OCF₃CHF₂ 3-F F F A-3342. OCF₃ CHF₂ 3-CH₃ F F A-3343. OCF₃ CHF₂ 3-OCH₃ F FA-3344. OCF₃ CHF₂ 5-F F F A-3345. OCF₃ CHF₂ 5-CH₃ F F A-3346. OCF₃ CHF₂5-OCH₃ F F A-3347. OCF₃ CF₃ 3-F F F A-3348. OCF₃ CF₃ 3-CH₃ F F A-3349.OCF₃ CF₃ 3-OCH₃ F F A-3350. OCF₃ CF₃ 5-F F F A-3351. OCF₃ CF₃ 5-CH₃ F FA-3352. OCF₃ CF₃ 5-OCH₃ F F A-3353. OCF₃ OCH₂F 3-F F F A-3354. OCF₃OCH₂F 3-CH₃ F F A-3355. OCF₃ OCH₂F 3-OCH₃ F F A-3356. OCF₃ OCH₂F 5-F F FA-3357. OCF₃ OCH₂F 5-CH₃ F F A-3358. OCF₃ OCH₂F 5-OCH₃ F F A-3359. OCF₃OCHF₂ 3-F F F A-3360. OCF₃ OCHF₂ 3-CH₃ F F A-3361. OCF₃ OCHF₂ 3-OCH₃ F FA-3362. OCF₃ OCHF₂ 5-F F F A-3363. OCF₃ OCHF₂ 5-CH₃ F F A-3364. OCF₃OCHF₂ 5-OCH₃ F F A-3365. OCF₃ OCF₃ 3-F F F A-3366. OCF₃ OCF₃ 3-CH₃ F FA-3367. OCF₃ OCF₃ 3-OCH₃ F F A-3368. OCF₃ OCF₃ 5-F F F A-3369. OCF₃ OCF₃5-CH₃ F F A-3370. OCF₃ OCF₃ 5-OCH₃ F F A-3371. H H H Cl F A-3372. F H HCl F A-3373. CH₃ H H Cl F A-3374. OCH₃ H H Cl F A-3375. CH₂F H H Cl FA-3376. CHF₂ H H Cl F A-3377. CF₃ H H Cl F A-3378. OCH₂F H H Cl FA-3379. OCHF₂ H H Cl F A-3380. OCF₃ H H Cl F A-3381. H F H Cl F A-3382.H CH₃ H Cl F A-3383. H OCH₃ H Cl F A-3384. H CN H Cl F A-3385. H CH₂F HCl F A-3386. H CHF₂ H Cl F A-3387. H CF₃ H Cl F A-3388. H OCH₂F H Cl FA-3389. H OCHF₂ H Cl F A-3390. H OCF₃ H Cl F A-3391. H H 3-F Cl FA-3392. H H 3-CH₃ Cl F A-3393. H H 3-OCH₃ Cl F A-3394. H H 5-F Cl FA-3395. H H 5-CH₃ Cl F A-3396. H H 5-OCH₃ Cl F A-3397. F F H Cl FA-3398. F CH₃ H Cl F A-3399. F OCH₃ H Cl F A-3400. F CN H Cl F A-3401. FCH₂F H Cl F A-3402. F CHF₂ H Cl F A-3403. F CF₃ H Cl F A-3404. F OCH₂F HCl F A-3405. F OCHF₂ H Cl F A-3406. F OCF₃ H Cl F A-3407. F H 3-F Cl FA-3408. F H 3-CH₃ Cl F A-3409. F H 3-OCH₃ Cl F A-3410. F H 5-F Cl FA-3411. F H 5-CH₃ Cl F A-3412. F H 5-OCH₃ Cl F A-3413. CH₃ F H Cl FA-3414. CH₃ CH₃ H Cl F A-3415. CH₃ OCH₃ H Cl F A-3416. CH₃ CN H Cl FA-3417. CH₃ CH₂F H Cl F A-3418. CH₃ CHF₂ H Cl F A-3419. CH₃ CF₃ H Cl FA-3420. CH₃ OCH₂F H Cl F A-3421. CH₃ OCHF₂ H Cl F A-3422. CH₃ OCF₃ H ClF A-3423. CH₃ H 3-F Cl F A-3424. CH₃ H 3-CH₃ Cl F A-3425. CH₃ H 3-OCH₃Cl F A-3426. CH₃ H 5-F Cl F A-3427. CH₃ H 5-CH₃ Cl F A-3428. CH₃ H5-OCH₃ Cl F A-3429. OCH₃ F H Cl F A-3430. OCH₃ CH₃ H Cl F A-3431. OCH₃OCH₃ H Cl F A-3432. OCH₃ CN H Cl F A-3433. OCH₃ CH₂F H Cl F A-3434. OCH₃CHF₂ H Cl F A-3435. OCH₃ CF₃ H Cl F A-3436. OCH₃ OCH₂F H Cl F A-3437.OCH₃ OCHF₂ H Cl F A-3438. OCH₃ OCF₃ H Cl F A-3439. OCH₃ H 3-F Cl FA-3440. OCH₃ H 3-CH₃ Cl F A-3441. OCH₃ H 3-OCH₃ Cl F A-3442. OCH₃ H 5-FCl F A-3443. OCH₃ H 5-CH₃ Cl F A-3444. OCH₃ H 5-OCH₃ Cl F A-3445. H F3-F Cl F A-3446. H F 3-CH₃ Cl F A-3447. H F 3-OCH₃ Cl F A-3448. H F 5-FCl F A-3449. H F 5-CH₃ Cl F A-3450. H F 5-OCH₃ Cl F A-3451. H CH₃ 3-F ClF A-3452. H CH₃ 3-CH₃ Cl F A-3453. H CH₃ 3-OCH₃ Cl F A-3454. H CH₃ 5-FCl F A-3455. H CH₃ 5-CH₃ Cl F A-3456. H CH₃ 5-OCH₃ Cl F A-3457. H OCH₃3-F Cl F A-3458. H OCH₃ 3-CH₃ Cl F A-3459. H OCH₃ 3-OCH₃ Cl F A-3460. HOCH₃ 5-F Cl F A-3461. H OCH₃ 5-CH₃ Cl F A-3462. H OCH₃ 5-OCH₃ Cl FA-3463. H CN 3-F Cl F A-3464. H CN 3-CH₃ Cl F A-3465. H CN 3-OCH₃ Cl FA-3466. H CN 5-F Cl F A-3467. H CN 5-CH₃ Cl F A-3468. H CN 5-OCH₃ Cl FA-3469. H CH₂F 3-F Cl F A-3470. H CH₂F 3-CH₃ Cl F A-3471. H CH₂F 3-OCH₃Cl F A-3472. H CH₂F 5-F Cl F A-3473. H CH₂F 5-CH₃ Cl F A-3474. H CH₂F5-OCH₃ Cl F A-3475. H CHF₂ 3-F Cl F A-3476. H CHF₂ 3-CH₃ Cl F A-3477. HCHF₂ 3-OCH₃ Cl F A-3478. H CHF₂ 5-F Cl F A-3479. H CHF₂ 5-CH₃ Cl FA-3480. H CHF₂ 5-OCH₃ Cl F A-3481. H CF₃ 3-F Cl F A-3482. H CF₃ 3-CH₃ ClF A-3483. H CF₃ 3-OCH₃ Cl F A-3484. H CF₃ 5-F Cl F A-3485. H CF₃ 5-CH₃Cl F A-3486. H CF₃ 5-OCH₃ Cl F A-3487. H OCH₂F 3-F Cl F A-3488. H OCH₂F3-CH₃ Cl F A-3489. H OCH₂F 3-OCH₃ Cl F A-3490. H OCH₂F 5-F Cl F A-3491.H OCH₂F 5-CH₃ Cl F A-3492. H OCH₂F 5-OCH₃ Cl F A-3493. H OCHF₂ 3-F Cl FA-3494. H OCHF₂ 3-CH₃ Cl F A-3495. H OCHF₂ 3-OCH₃ Cl F A-3496. H OCHF₂5-F Cl F A-3497. H OCHF₂ 5-CH₃ Cl F A-3498. H OCHF₂ 5-OCH₃ Cl F A-3499.H OCF₃ 3-F Cl F A-3500. H OCF₃ 3-CH₃ Cl F A-3501. H OCF₃ 3-OCH₃ Cl FA-3502. H OCF₃ 5-F Cl F A-3503. H OCF₃ 5-CH₃ Cl F A-3504. H OCF₃ 5-OCH₃Cl F A-3505. F F 3-F Cl F A-3506. F F 3-CH₃ Cl F A-3507. F F 3-OCH₃ Cl FA-3508. F F 5-F Cl F A-3509. F F 5-CH₃ Cl F A-3510. F F 5-OCH₃ Cl FA-3511. F CH₃ 3-F Cl F A-3512. F CH₃ 3-CH₃ Cl F A-3513. F CH₃ 3-OCH₃ ClF A-3514. F CH₃ 5-F Cl F A-3515. F CH₃ 5-CH₃ Cl F A-3516. F CH₃ 5-OCH₃Cl F A-3517. F OCH₃ 3-F Cl F A-3518. F OCH₃ 3-CH₃ Cl F A-3519. F OCH₃3-OCH₃ Cl F A-3520. F OCH₃ 5-F Cl F A-3521. F OCH₃ 5-CH₃ Cl F A-3522. FOCH₃ 5-OCH₃ Cl F A-3523. F CN 3-F Cl F A-3524. F CN 3-CH₃ Cl F A-3525. FCN 3-OCH₃ Cl F A-3526. F CN 5-F Cl F A-3527. F CN 5-CH₃ Cl F A-3528. FCN 5-OCH₃ Cl F A-3529. F CH₂F 3-F Cl F A-3530. F CH₂F 3-CH₃ Cl F A-3531.F CH₂F 3-OCH₃ Cl F A-3532. F CH₂F 5-F Cl F A-3533. F CH₂F 5-CH₃ Cl FA-3534. F CH₂F 5-OCH₃ Cl F A-3535. F CHF₂ 3-F Cl F A-3536. F CHF₂ 3-CH₃Cl F A-3537. F CHF₂ 3-OCH₃ Cl F A-3538. F CHF₂ 5-F Cl F A-3539. F CHF₂5-CH₃ Cl F A-3540. F CHF₂ 5-OCH₃ Cl F A-3541. F CF₃ 3-F Cl F A-3542. FCF₃ 3-CH₃ Cl F A-3543. F CF₃ 3-OCH₃ Cl F A-3544. F CF₃ 5-F Cl F A-3545.F CF₃ 5-CH₃ Cl F A-3546. F CF₃ 5-OCH₃ Cl F A-3547. F OCH₂F 3-F Cl FA-3548. F OCH₂F 3-CH₃ Cl F A-3549. F OCH₂F 3-OCH₃ Cl F A-3550. F OCH₂F5-F Cl F A-3551. F OCH₂F 5-CH₃ Cl F A-3552. F OCH₂F 5-OCH₃ Cl F A-3553.F OCHF₂ 3-F Cl F A-3554. F OCHF₂ 3-CH₃ Cl F A-3555. F OCHF₂ 3-OCH₃ Cl FA-3556. F OCHF₂ 5-F Cl F A-3557. F OCHF₂ 5-CH₃ Cl F A-3558. F OCHF₂5-OCH₃ Cl F A-3559. F OCF₃ 3-F Cl F A-3560. F OCF₃ 3-CH₃ Cl F A-3561. FOCF₃ 3-OCH₃ Cl F A-3562. F OCF₃ 5-F Cl F A-3563. F OCF₃ 5-CH₃ Cl FA-3564. F OCF₃ 5-OCH₃ Cl F A-3565. CH₃ F 3-F Cl F A-3566. CH₃ F 3-CH₃ ClF A-3567. CH₃ F 3-OCH₃ Cl F A-3568. CH₃ F 5-F Cl F A-3569. CH₃ F 5-CH₃Cl F A-3570. CH₃ F 5-OCH₃ Cl F A-3571. CH₃ CH₃ 3-F Cl F A-3572. CH₃ CH₃3-CH₃ Cl F A-3573. CH₃ CH₃ 3-OCH₃ Cl F A-3574. CH₃ CH₃ 5-F Cl F A-3575.CH₃ CH₃ 5-CH₃ Cl F A-3576. CH₃ CH₃ 5-OCH₃ Cl F A-3577. CH₃ OCH₃ 3-F Cl FA-3578. CH₃ OCH₃ 3-CH₃ Cl F A-3579. CH₃ OCH₃ 3-OCH₃ Cl F A-3580. CH₃OCH₃ 5-F Cl F A-3581. CH₃ OCH₃ 5-CH₃ Cl F A-3582. CH₃ OCH₃ 5-OCH₃ Cl FA-3583. CH₃ CN 3-F Cl F A-3584. CH₃ CN 3-CH₃ Cl F A-3585. CH₃ CN 3-OCH₃Cl F A-3586. CH₃ CN 5-F Cl F A-3587. CH₃ CN 5-CH₃ Cl F A-3588. CH₃ CN5-OCH₃ Cl F A-3589. CH₃ CH₂F 3-F Cl F A-3590. CH₃ CH₂F 3-CH₃ Cl FA-3591. CH₃ CH₂F 3-OCH₃ Cl F A-3592. CH₃ CH₂F 5-F Cl F A-3593. CH₃ CH₂F5-CH₃ Cl F A-3594. CH₃ CH₂F 5-OCH₃ Cl F A-3595. CH₃ CHF₂ 3-F Cl FA-3596. CH₃ CHF₂ 3-CH₃ Cl F A-3597. CH₃ CHF₂ 3-OCH₃ Cl F A-3598. CH₃CHF₂ 5-F Cl F A-3599. CH₃ CHF₂ 5-CH₃ Cl F A-3600. CH₃ CHF₂ 5-OCH₃ Cl FA-3601. CH₃ CF₃ 3-F Cl F A-3602. CH₃ CF₃ 3-CH₃ Cl F A-3603. CH₃ CF₃3-OCH₃ Cl F A-3604. CH₃ CF₃ 5-F Cl F A-3605. CH₃ CF₃ 5-CH₃ Cl F A-3606.CH₃ CF₃ 5-OCH₃ Cl F A-3607. CH₃ OCH₂F 3-F Cl F A-3608. CH₃ OCH₂F 3-CH₃Cl F A-3609. CH₃ OCH₂F 3-OCH₃ Cl F A-3610. CH₃ OCH₂F 5-F Cl F A-3611.CH₃ OCH₂F 5-CH₃ Cl F A-3612. CH₃ OCH₂F 5-OCH₃ Cl F A-3613. CH₃ OCHF₂ 3-FCl F A-3614. CH₃ OCHF₂ 3-CH₃ Cl F A-3615. CH₃ OCHF₂ 3-OCH₃ Cl F A-3616.CH₃ OCHF₂ 5-F Cl F A-3617. CH₃ OCHF₂ 5-CH₃ Cl F A-3618. CH₃ OCHF₂ 5-OCH₃Cl F A-3619. CH₃ OCF₃ 3-F Cl F A-3620. CH₃ OCF₃ 3-CH₃ Cl F A-3621. CH₃OCF₃ 3-OCH₃ Cl F A-3622. CH₃ OCF₃ 5-F Cl F A-3623. CH₃ OCF₃ 5-CH₃ Cl FA-3624. CH₃ OCF₃ 5-OCH₃ Cl F A-3625. OCH₃ F 3-F Cl F A-3626. OCH₃ F3-CH₃ Cl F A-3627. OCH₃ F 3-OCH₃ Cl F A-3628. OCH₃ F 5-F Cl F A-3629.OCH₃ F 5-CH₃ Cl F A-3630. OCH₃ F 5-OCH₃ Cl F A-3631. OCH₃ CH₃ 3-F Cl FA-3632. OCH₃ CH₃ 3-CH₃ Cl F A-3633. OCH₃ CH₃ 3-OCH₃ Cl F A-3634. OCH₃CH₃ 5-F Cl F A-3635. OCH₃ CH₃ 5-CH₃ Cl F A-3636. OCH₃ CH₃ 5-OCH₃ Cl FA-3637. OCH₃ OCH₃ 3-F Cl F A-3638. OCH₃ OCH₃ 3-CH₃ Cl F A-3639. OCH₃OCH₃ 3-OCH₃ Cl F A-3640. OCH₃ OCH₃ 5-F Cl F A-3641. OCH₃ OCH₃ 5-CH₃ Cl FA-3642. OCH₃ OCH₃ 5-OCH₃ Cl F A-3643. OCH₃ CN 3-F Cl F A-3644. OCH₃ CN3-CH₃ Cl F A-3645. OCH₃ CN 3-OCH₃ Cl F A-3646. OCH₃ CN 5-F Cl F A-3647.OCH₃ CN 5-CH₃ Cl F A-3648. OCH₃ CN 5-OCH₃ Cl F A-3649. OCH₃ CH₂F 3-F ClF A-3650. OCH₃ CH₂F 3-CH₃ Cl F A-3651. OCH₃ CH₂F 3-OCH₃ Cl F A-3652.OCH₃ CH₂F 5-F Cl F A-3653. OCH₃ CH₂F 5-CH₃ Cl F A-3654. OCH₃ CH₂F 5-OCH₃Cl F A-3655. OCH₃ CHF₂ 3-F Cl F A-3656. OCH₃ CHF₂ 3-CH₃ Cl F A-3657.OCH₃ CHF₂ 3-OCH₃ Cl F A-3658. OCH₃ CHF₂ 5-F Cl F A-3659. OCH₃ CHF₂ 5-CH₃Cl F A-3660. OCH₃ CHF₂ 5-OCH₃ Cl F A-3661. OCH₃ CF₃ 3-F Cl F A-3662.OCH₃ CF₃ 3-CH₃ Cl F A-3663. OCH₃ CF₃ 3-OCH₃ Cl F A-3664. OCH₃ CF₃ 5-F ClF A-3665. OCH₃ CF₃ 5-CH₃ Cl F A-3666. OCH₃ CF₃ 5-OCH₃ Cl F A-3667. OCH₃OCH₂F 3-F Cl F A-3668. OCH₃ OCH₂F 3-CH₃ Cl F A-3669. OCH₃ OCH₂F 3-OCH₃Cl F A-3670. OCH₃ OCH₂F 5-F Cl F A-3671. OCH₃ OCH₂F 5-CH₃ Cl F A-3672.OCH₃ OCH₂F 5-OCH₃ Cl F A-3673. OCH₃ OCHF₂ 3-F Cl F A-3674. OCH₃ OCHF₂3-CH₃ Cl F A-3675. OCH₃ OCHF₂ 3-OCH₃ Cl F A-3676. OCH₃ OCHF₂ 5-F Cl FA-3677. OCH₃ OCHF₂ 5-CH₃ Cl F A-3678. OCH₃ OCHF₂ 5-OCH₃ Cl F A-3679.OCH₃ OCF₃ 3-F Cl F A-3680. OCH₃ OCF₃ 3-CH₃ Cl F A-3681. OCH₃ OCF₃ 3-OCH₃Cl F A-3682. OCH₃ OCF₃ 5-F Cl F A-3683. OCH₃ OCF₃ 5-CH₃ Cl F A-3684.OCH₃ OCF₃ 5-OCH₃ Cl F A-3685. CH₂F F 3-F Cl F A-3686. CH₂F F 3-CH₃ Cl FA-3687. CH₂F F 3-OCH₃ Cl F A-3688. CH₂F F 5-F Cl F A-3689. CH₂F F 5-CH₃Cl F A-3690. CH₂F F 5-OCH₃ Cl F A-3691. CH₂F CH₃ 3-F Cl F A-3692. CH₂FCH₃ 3-CH₃ Cl F A-3693. CH₂F CH₃ 3-OCH₃ Cl F A-3694. CH₂F CH₃ 5-F Cl FA-3695. CH₂F CH₃ 5-CH₃ Cl F A-3696. CH₂F CH₃ 5-OCH₃ Cl F A-3697. CH₂FOCH₃ 3-F Cl F A-3698. CH₂F OCH₃ 3-CH₃ Cl F A-3699. CH₂F OCH₃ 3-OCH₃ Cl FA-3700. CH₂F OCH₃ 5-F Cl F A-3701. CH₂F OCH₃ 5-CH₃ Cl F A-3702. CH₂FOCH₃ 5-OCH₃ Cl F A-3703. CH₂F CN 3-F Cl F A-3704. CH₂F CN 3-CH₃ Cl FA-3705. CH₂F CN 3-OCH₃ Cl F A-3706. CH₂F CN 5-F Cl F A-3707. CH₂F CN5-CH₃ Cl F A-3708. CH₂F CN 5-OCH₃ Cl F A-3709. CH₂F CH₂F 3-F Cl FA-3710. CH₂F CH₂F 3-CH₃ Cl F A-3711. CH₂F CH₂F 3-OCH₃ Cl F A-3712. CH₂FCH₂F 5-F Cl F A-3713. CH₂F CH₂F 5-CH₃ Cl F A-3714. CH₂F CH₂F 5-OCH₃ Cl FA-3715. CH₂F CHF₂ 3-F Cl F A-3716. CH₂F CHF₂ 3-CH₃ Cl F A-3717. CH₂FCHF₂ 3-OCH₃ Cl F A-3718. CH₂F CHF₂ 5-F Cl F A-3719. CH₂F CHF₂ 5-CH₃ Cl FA-3720. CH₂F CHF₂ 5-OCH₃ Cl F A-3721. CH₂F CF₃ 3-F Cl F A-3722. CH₂F CF₃3-CH₃ Cl F A-3723. CH₂F CF₃ 3-OCH₃ Cl F A-3724. CH₂F CF₃ 5-F Cl FA-3725. CH₂F CF₃ 5-CH₃ Cl F A-3726. CH₂F CF₃ 5-OCH₃ Cl F A-3727. CH₂FOCH₂F 3-F Cl F A-3728. CH₂F OCH₂F 3-CH₃ Cl F A-3729. CH₂F OCH₂F 3-OCH₃Cl F A-3730. CH₂F OCH₂F 5-F Cl F A-3731. CH₂F OCH₂F 5-CH₃ Cl F A-3732.CH₂F OCH₂F 5-OCH₃ Cl F A-3733. CH₂F OCHF₂ 3-F Cl F A-3734. CH₂F OCHF₂3-CH₃ Cl F A-3735. CH₂F OCHF₂ 3-OCH₃ Cl F A-3736. CH₂F OCHF₂ 5-F Cl FA-3737. CH₂F OCHF₂ 5-CH₃ Cl F A-3738. CH₂F OCHF₂ 5-OCH₃ Cl F A-3739.CH₂F OCF₃ 3-F Cl F A-3740. CH₂F OCF₃ 3-CH₃ Cl F A-3741. CH₂F OCF₃ 3-OCH₃Cl F A-3742. CH₂F OCF₃ 5-F Cl F A-3743. CH₂F OCF₃ 5-CH₃ Cl F A-3744.CH₂F OCF₃ 5-OCH₃ Cl F A-3745. CHF₂ F 3-F Cl F A-3746. CHF₂ F 3-CH₃ Cl FA-3747. CHF₂ F 3-OCH₃ Cl F A-3748. CHF₂ F 5-F Cl F A-3749. CHF₂ F 5-CH₃Cl F A-3750. CHF₂ F 5-OCH₃ Cl F A-3751. CHF₂ CH₃ 3-F Cl F A-3752. CHF₂CH₃ 3-CH₃ Cl F A-3753. CHF₂ CH₃ 3-OCH₃ Cl F A-3754. CHF₂ CH₃ 5-F Cl FA-3755. CHF₂ CH₃ 5-CH₃ Cl F A-3756. CHF₂ CH₃ 5-OCH₃ Cl F A-3757. CHF₂OCH₃ 3-F Cl F A-3758. CHF₂ OCH₃ 3-CH₃ Cl F A-3759. CHF₂ OCH₃ 3-OCH₃ Cl FA-3760. CHF₂ OCH₃ 5-F Cl F A-3761. CHF₂ OCH₃ 5-CH₃ Cl F A-3762. CHF₂OCH₃ 5-OCH₃ Cl F A-3763. CHF₂ CN 3-F Cl F A-3764. CHF₂ CN 3-CH₃ Cl FA-3765. CHF₂ CN 3-OCH₃ Cl F A-3766. CHF₂ CN 5-F Cl F A-3767. CHF₂ CN5-CH₃ Cl F A-3768. CHF₂ CN 5-OCH₃ Cl F A-3769. CHF₂ CH₂F 3-F Cl FA-3770. CHF₂ CH₂F 3-CH₃ Cl F A-3771. CHF₂ CH₂F 3-OCH₃ Cl F A-3772. CHF₂CH₂F 5-F Cl F A-3773. CHF₂ CH₂F 5-CH₃ Cl F A-3774. CHF₂ CH₂F 5-OCH₃ Cl FA-3775. CHF₂ CHF₂ 3-F Cl F A-3776. CHF₂ CHF₂ 3-CH₃ Cl F A-3777. CHF₂CHF₂ 3-OCH₃ Cl F A-3778. CHF₂ CHF₂ 5-F Cl F A-3779. CHF₂ CHF₂ 5-CH₃ Cl FA-3780. CHF₂ CHF₂ 5-OCH₃ Cl F A-3781. CHF₂ CF₃ 3-F Cl F A-3782. CHF₂ CF₃3-CH₃ Cl F A-3783. CHF₂ CF₃ 3-OCH₃ Cl F A-3784. CHF₂ CF₃ 5-F Cl FA-3785. CHF₂ CF₃ 5-CH₃ Cl F A-3786. CHF₂ CF₃ 5-OCH₃ Cl F A-3787. CHF₂OCH₂F 3-F Cl F A-3788. CHF₂ OCH₂F 3-CH₃ Cl F A-3789. CHF₂ OCH₂F 3-OCH₃Cl F A-3790. CHF₂ OCH₂F 5-F Cl F A-3791. CHF₂ OCH₂F 5-CH₃ Cl F A-3792.CHF₂ OCH₂F 5-OCH₃ Cl F A-3793. CHF₂ OCHF₂ 3-F Cl F A-3794. CHF₂ OCHF₂3-CH₃ Cl F A-3795. CHF₂ OCHF₂ 3-OCH₃ Cl F A-3796. CHF₂ OCHF₂ 5-F Cl FA-3797. CHF₂ OCHF₂ 5-CH₃ Cl F A-3798. CHF₂ OCHF₂ 5-OCH₃ Cl F A-3799.CHF₂ OCF₃ 3-F Cl F A-3800. CHF₂ OCF₃ 3-CH₃ Cl F A-3801. CHF₂ OCF₃ 3-OCH₃Cl F A-3802. CHF₂ OCF₃ 5-F Cl F A-3803. CHF₂ OCF₃ 5-CH₃ Cl F A-3804.CHF₂ OCF₃ 5-OCH₃ Cl F A-3805. CF₃ F 3-F Cl F A-3806. CF₃ F 3-CH₃ Cl FA-3807. CF₃ F 3-OCH₃ Cl F A-3808. CF₃ F 5-F Cl F A-3809. CF₃ F 5-CH₃ ClF A-3810. CF₃ F 5-OCH₃ Cl F A-3811. CF₃ CH₃ 3-F Cl F A-3812. CF₃ CH₃3-CH₃ Cl F A-3813. CF₃ CH₃ 3-OCH₃ Cl F A-3814. CF₃ CH₃ 5-F Cl F A-3815.CF₃ CH₃ 5-CH₃ Cl F A-3816. CF₃ CH₃ 5-OCH₃ Cl F A-3817. CF₃ OCH₃ 3-F Cl FA-3818. CF₃ OCH₃ 3-CH₃ Cl F A-3819. CF₃ OCH₃ 3-OCH₃ Cl F A-3820. CF₃OCH₃ 5-F Cl F A-3821. CF₃ OCH₃ 5-CH₃ Cl F A-3822. CF₃ OCH₃ 5-OCH₃ Cl FA-3823. CF₃ CN 3-F Cl F A-3824. CF₃ CN 3-CH₃ Cl F A-3825. CF₃ CN 3-OCH₃Cl F A-3826. CF₃ CN 5-F Cl F A-3827. CF₃ CN 5-CH₃ Cl F A-3828. CF₃ CN5-OCH₃ Cl F A-3829. CF₃ CH₂F 3-F Cl F A-3830. CF₃ CH₂F 3-CH₃ Cl FA-3831. CF₃ CH₂F 3-OCH₃ Cl F A-3832. CF₃ CH₂F 5-F Cl F A-3833. CF₃ CH₂F5-CH₃ Cl F A-3834. CF₃ CH₂F 5-OCH₃ Cl F A-3835. CF₃ CHF₂ 3-F Cl FA-3836. CF₃ CHF₂ 3-CH₃ Cl F A-3837. CF₃ CHF₂ 3-OCH₃ Cl F A-3838. CF₃CHF₂ 5-F Cl F A-3839. CF₃ CHF₂ 5-CH₃ Cl F A-3840. CF₃ CHF₂ 5-OCH₃ Cl FA-3841. CF₃ CF₃ 3-F Cl F A-3842. CF₃ CF₃ 3-CH₃ Cl F A-3843. CF₃ CF₃3-OCH₃ Cl F A-3844. CF₃ CF₃ 5-F Cl F A-3845. CF₃ CF₃ 5-CH₃ Cl F A-3846.CF₃ CF₃ 5-OCH₃ Cl F A-3847. CF₃ OCH₂F 3-F Cl F A-3848. CF₃ OCH₂F 3-CH₃Cl F A-3849. CF₃ OCH₂F 3-OCH₃ Cl F A-3850. CF₃ OCH₂F 5-F Cl F A-3851.CF₃ OCH₂F 5-CH₃ Cl F A-3852. CF₃ OCH₂F 5-OCH₃ Cl F A-3853. CF₃ OCHF₂ 3-FCl F A-3854. CF₃ OCHF₂ 3-CH₃ Cl F A-3855. CF₃ OCHF₂ 3-OCH₃ Cl F A-3856.CF₃ OCHF₂ 5-F Cl F A-3857. CF₃ OCHF₂ 5-CH₃ Cl F A-3858. CF₃ OCHF₂ 5-OCH₃Cl F A-3859. CF₃ OCF₃ 3-F Cl F A-3860. CF₃ OCF₃ 3-CH₃ Cl F A-3861. CF₃OCF₃ 3-OCH₃ Cl F A-3862. CF₃ OCF₃ 5-F Cl F A-3863. CF₃ OCF₃ 5-CH₃ Cl FA-3864. CF₃ OCF₃ 5-OCH₃ Cl F A-3865. OCH₂F F 3-F Cl F A-3866. OCH₂F F3-CH₃ Cl F A-3867. OCH₂F F 3-OCH₃ Cl F A-3868. OCH₂F F 5-F Cl F A-3869.OCH₂F F 5-CH₃ Cl F A-3870. OCH₂F F 5-OCH₃ Cl F A-3871. OCH₂F CH₃ 3-F ClF A-3872. OCH₂F CH₃ 3-CH₃ Cl F A-3873. OCH₂F CH₃ 3-OCH₃ Cl F A-3874.OCH₂F CH₃ 5-F Cl F A-3875. OCH₂F CH₃ 5-CH₃ Cl F A-3876. OCH₂F CH₃ 5-OCH₃Cl F A-3877. OCH₂F OCH₃ 3-F Cl F A-3878. OCH₂F OCH₃ 3-CH₃ Cl F A-3879.OCH₂F OCH₃ 3-OCH₃ Cl F A-3880. OCH₂F OCH₃ 5-F Cl F A-3881. OCH₂F OCH₃5-CH₃ Cl F A-3882. OCH₂F OCH₃ 5-OCH₃ Cl F A-3883. OCH₂F CN 3-F Cl FA-3884. OCH₂F CN 3-CH₃ Cl F A-3885. OCH₂F CN 3-OCH₃ Cl F A-3886. OCH₂FCN 5-F Cl F A-3887. OCH₂F CN 5-CH₃ Cl F A-3888. OCH₂F CN 5-OCH₃ Cl FA-3889. OCH₂F CH₂F 3-F Cl F A-3890. OCH₂F CH₂F 3-CH₃ Cl F A-3891. OCH₂FCH₂F 3-OCH₃ Cl F A-3892. OCH₂F CH₂F 5-F Cl F A-3893. OCH₂F CH₂F 5-CH₃ ClF A-3894. OCH₂F CH₂F 5-OCH₃ Cl F A-3895. OCH₂F CHF₂ 3-F Cl F A-3896.OCH₂F CHF₂ 3-CH₃ Cl F A-3897. OCH₂F CHF₂ 3-OCH₃ Cl F A-3898. OCH₂F CHF₂5-F Cl F A-3899. OCH₂F CHF₂ 5-CH₃ Cl F A-3900. OCH₂F CHF₂ 5-OCH₃ Cl FA-3901. OCH₂F CF₃ 3-F Cl F A-3902. OCH₂F CF₃ 3-CH₃ Cl F A-3903. OCH₂FCF₃ 3-OCH₃ Cl F A-3904. OCH₂F CF₃ 5-F Cl F A-3905. OCH₂F CF₃ 5-CH₃ Cl FA-3906. OCH₂F CF₃ 5-OCH₃ Cl F A-3907. OCH₂F OCH₂F 3-F Cl F A-3908. OCH₂FOCH₂F 3-CH₃ Cl F A-3909. OCH₂F OCH₂F 3-OCH₃ Cl F A-3910. OCH₂F OCH₂F 5-FCl F A-3911. OCH₂F OCH₂F 5-CH₃ Cl F A-3912. OCH₂F OCH₂F 5-OCH₃ Cl FA-3913. OCH₂F OCHF₂ 3-F Cl F A-3914. OCH₂F OCHF₂ 3-CH₃ Cl F A-3915.OCH₂F OCHF₂ 3-OCH₃ Cl F A-3916. OCH₂F OCHF₂ 5-F Cl F A-3917. OCH₂F OCHF₂5-CH₃ Cl F A-3918. OCH₂F OCHF₂ 5-OCH₃ Cl F A-3919. OCH₂F OCF₃ 3-F Cl FA-3920. OCH₂F OCF₃ 3-CH₃ Cl F A-3921. OCH₂F OCF₃ 3-OCH₃ Cl F A-3922.OCH₂F OCF₃ 5-F Cl F A-3923. OCH₂F OCF₃ 5-CH₃ Cl F A-3924. OCH₂F OCF₃5-OCH₃ Cl F A-3925. OCHF₂ F 3-F Cl F A-3926. OCHF₂ F 3-CH₃ Cl F A-3927.OCHF₂ F 3-OCH₃ Cl F A-3928. OCHF₂ F 5-F Cl F A-3929. OCHF₂ F 5-CH₃ Cl FA-3930. OCHF₂ F 5-OCH₃ Cl F A-3931. OCHF₂ CH₃ 3-F Cl F A-3932. OCHF₂ CH₃3-CH₃ Cl F A-3933. OCHF₂ CH₃ 3-OCH₃ Cl F A-3934. OCHF₂ CH₃ 5-F Cl FA-3935. OCHF₂ CH₃ 5-CH₃ Cl F A-3936. OCHF₂ CH₃ 5-OCH₃ Cl F A-3937. OCHF₂OCH₃ 3-F Cl F A-3938. OCHF₂ OCH₃ 3-CH₃ Cl F A-3939. OCHF₂ OCH₃ 3-OCH₃ ClF A-3940. OCHF₂ OCH₃ 5-F Cl F A-3941. OCHF₂ OCH₃ 5-CH₃ Cl F A-3942.OCHF₂ OCH₃ 5-OCH₃ Cl F A-3943. OCHF₂ CN 3-F Cl F A-3944. OCHF₂ CN 3-CH₃Cl F A-3945. OCHF₂ CN 3-OCH₃ Cl F A-3946. OCHF₂ CN 5-F Cl F A-3947.OCHF₂ CN 5-CH₃ Cl F A-3948. OCHF₂ CN 5-OCH₃ Cl F A-3949. OCHF₂ CH₂F 3-FCl F A-3950. OCHF₂ CH₂F 3-CH₃ Cl F A-3951. OCHF₂ CH₂F 3-OCH₃ Cl FA-3952. OCHF₂ CH₂F 5-F Cl F A-3953. OCHF₂ CH₂F 5-CH₃ Cl F A-3954. OCHF₂CH₂F 5-OCH₃ Cl F A-3955. OCHF₂ CHF₂ 3-F Cl F A-3956. OCHF₂ CHF₂ 3-CH₃ ClF A-3957. OCHF₂ CHF₂ 3-OCH₃ Cl F A-3958. OCHF₂ CHF₂ 5-F Cl F A-3959.OCHF₂ CHF₂ 5-CH₃ Cl F A-3960. OCHF₂ CHF₂ 5-OCH₃ Cl F A-3961. OCHF₂ CF₃3-F Cl F A-3962. OCHF₂ CF₃ 3-CH₃ Cl F A-3963. OCHF₂ CF₃ 3-OCH₃ Cl FA-3964. OCHF₂ CF₃ 5-F Cl F A-3965. OCHF₂ CF₃ 5-CH₃ Cl F A-3966. OCHF₂CF₃ 5-OCH₃ Cl F A-3967. OCHF₂ OCH₂F 3-F Cl F A-3968. OCHF₂ OCH₂F 3-CH₃Cl F A-3969. OCHF₂ OCH₂F 3-OCH₃ Cl F A-3970. OCHF₂ OCH₂F 5-F Cl FA-3971. OCHF₂ OCH₂F 5-CH₃ Cl F A-3972. OCHF₂ OCH₂F 5-OCH₃ Cl F A-3973.OCHF₂ OCHF₂ 3-F Cl F A-3974. OCHF₂ OCHF₂ 3-CH₃ Cl F A-3975. OCHF₂ OCHF₂3-OCH₃ Cl F A-3976. OCHF₂ OCHF₂ 5-F Cl F A-3977. OCHF₂ OCHF₂ 5-CH₃ Cl FA-3978. OCHF₂ OCHF₂ 5-OCH₃ Cl F A-3979. OCHF₂ OCF₃ 3-F Cl F A-3980.OCHF₂ OCF₃ 3-CH₃ Cl F A-3981. OCHF₂ OCF₃ 3-OCH₃ Cl F A-3982. OCHF₂ OCF₃5-F Cl F A-3983. OCHF₂ OCF₃ 5-CH₃ Cl F A-3984. OCHF₂ OCF₃ 5-OCH₃ Cl FA-3985. OCF₃ F 3-F Cl F A-3986. OCF₃ F 3-CH₃ Cl F A-3987. OCF₃ F 3-OCH₃Cl F A-3988. OCF₃ F 5-F Cl F A-3989. OCF₃ F 5-CH₃ Cl F A-3990. OCF₃ F5-OCH₃ Cl F A-3991. OCF₃ CH₃ 3-F Cl F A-3992. OCF₃ CH₃ 3-CH₃ Cl FA-3993. OCF₃ CH₃ 3-OCH₃ Cl F A-3994. OCF₃ CH₃ 5-F Cl F A-3995. OCF₃ CH₃5-CH₃ Cl F A-3996. OCF₃ CH₃ 5-OCH₃ Cl F A-3997. OCF₃ OCH₃ 3-F Cl FA-3998. OCF₃ OCH₃ 3-CH₃ Cl F A-3999. OCF₃ OCH₃ 3-OCH₃ Cl F A-4000. OCF₃OCH₃ 5-F Cl F A-4001. OCF₃ OCH₃ 5-CH₃ Cl F A-4002. OCF₃ OCH₃ 5-OCH₃ Cl FA-4003. OCF₃ CN 3-F Cl F A-4004. OCF₃ CN 3-CH₃ Cl F A-4005. OCF₃ CN3-OCH₃ Cl F A-4006. OCF₃ CN 5-F Cl F A-4007. OCF₃ CN 5-CH₃ Cl F A-4008.OCF₃ CN 5-OCH₃ Cl F A-4009. OCF₃ CH₂F 3-F Cl F A-4010. OCF₃ CH₂F 3-CH₃Cl F A-4011. OCF₃ CH₂F 3-OCH₃ Cl F A-4012. OCF₃ CH₂F 5-F Cl F A-4013.OCF₃ CH₂F 5-CH₃ Cl F A-4014. OCF₃ CH₂F 5-OCH₃ Cl F A-4015. OCF₃ CHF₂ 3-FCl F A-4016. OCF₃ CHF₂ 3-CH₃ Cl F A-4017. OCF₃ CHF₂ 3-OCH₃ Cl F A-4018.OCF₃ CHF₂ 5-F Cl F A-4019. OCF₃ CHF₂ 5-CH₃ Cl F A-4020. OCF₃ CHF₂ 5-OCH₃Cl F A-4021. OCF₃ CF₃ 3-F Cl F A-4022. OCF₃ CF₃ 3-CH₃ Cl F A-4023. OCF₃CF₃ 3-OCH₃ Cl F A-4024. OCF₃ CF₃ 5-F Cl F A-4025. OCF₃ CF₃ 5-CH₃ Cl FA-4026. OCF₃ CF₃ 5-OCH₃ Cl F A-4027. OCF₃ OCH₂F 3-F Cl F A-4028. OCF₃OCH₂F 3-CH₃ Cl F A-4029. OCF₃ OCH₂F 3-OCH₃ Cl F A-4030. OCF₃ OCH₂F 5-FCl F A-4031. OCF₃ OCH₂F 5-CH₃ Cl F A-4032. OCF₃ OCH₂F 5-OCH₃ Cl FA-4033. OCF₃ OCHF₂ 3-F Cl F A-4034. OCF₃ OCHF₂ 3-CH₃ Cl F A-4035. OCF₃OCHF₂ 3-OCH₃ Cl F A-4036. OCF₃ OCHF₂ 5-F Cl F A-4037. OCF₃ OCHF₂ 5-CH₃Cl F A-4038. OCF₃ OCHF₂ 5-OCH₃ Cl F A-4039. OCF₃ OCF₃ 3-F Cl F A-4040.OCF₃ OCF₃ 3-CH₃ Cl F A-4041. OCF₃ OCF₃ 3-OCH₃ Cl F A-4042. OCF₃ OCF₃ 5-FCl F A-4043. OCF₃ OCF₃ 5-CH₃ Cl F A-4044. OCF₃ OCF₃ 5-OCH₃ Cl F

TABLE B Example No. R² R³ R⁶ R⁷ B-1. H H CN H B-2. F H CN H B-3. CH₃ HCN H B-4. OCH₃ H CN H B-5. CN H CN H B-6. CH₂F H CN H B-7. CHF₂ H CN HB-8. CF₃ H CN H B-9. OCH₂F H CN H B-10. OCHF₂ H CN H B-11. OCF₃ H CN HB-12. H 3-F CN H B-13. H 3-CH₃ CN H B-14. H 3-OCH₃ CN H B-15. H 5-F CN HB-16. H 5-CH₃ CN H B-17. H 5-OCH₃ CN H B-18. H 6-F CN H B-19. H 6-CH₃ CNH B-20. H 6-OCH₃ CN H B-21. F 3-F CN H B-22. F 3-CH₃ CN H B-23. F 3-OCH₃CN H B-24. F 5-F CN H B-25. F 5-CH₃ CN H B-26. F 5-OCH₃ CN H B-27. F 6-FCN H B-28. F 6-CH₃ CN H B-29. F 6-OCH₃ CN H B-30. CH₃ 3-F CN H B-31. CH₃3-CH₃ CN H B-32. CH₃ 3-OCH₃ CN H B-33. CH₃ 5-F CN H B-34. CH₃ 5-CH₃ CN HB-35. CH₃ 5-OCH₃ CN H B-36. CH₃ 6-F CN H B-37. CH₃ 6-CH₃ CN H B-38. CH₃6-OCH₃ CN H B-39. OCH₃ 3-F CN H B-40. OCH₃ 3-CH₃ CN H B-41. OCH₃ 3-OCH₃CN H B-42. OCH₃ 5-F CN H B-43. OCH₃ 5-CH₃ CN H B-44. OCH₃ 5-OCH₃ CN HB-45. OCH₃ 6-F CN H B-46. OCH₃ 6-CH₃ CN H B-47. OCH₃ 6-OCH₃ CN H B-48.CN 3-F CN H B-49. CN 3-CH₃ CN H B-50. CN 3-OCH₃ CN H B-51. CN 5-F CN HB-52. CN 5-CH₃ CN H B-53. CN 5-OCH₃ CN H B-54. CN 6-F CN H B-55. CN6-CH₃ CN H B-56. CN 6-OCH₃ CN H B-57. CH₂F 3-F CN H B-58. CH₂F 3-CH₃ CNH B-59. CH₂F 3-OCH₃ CN H B-60. CH₂F 5-F CN H B-61. CH₂F 5-CH₃ CN H B-62.CH₂F 5-OCH₃ CN H B-63. CH₂F 6-F CN H B-64. CH₂F 6-CH₃ CN H B-65. CH₂F6-OCH₃ CN H B-66. CHF₂ 3-F CN H B-67. CHF₂ 3-CH₃ CN H B-68. CHF₂ 3-OCH₃CN H B-69. CHF₂ 5-F CN H B-70. CHF₂ 5-CH₃ CN H B-71. CHF₂ 5-OCH₃ CN HB-72. CHF₂ 6-F CN H B-73. CHF₂ 6-CH₃ CN H B-74. CHF₂ 6-OCH₃ CN H B-75.CF₃ 3-F CN H B-76. CF₃ 3-CH₃ CN H B-77. CF₃ 3-OCH₃ CN H B-78. CF₃ 5-F CNH B-79. CF₃ 5-CH₃ CN H B-80. CF₃ 5-OCH₃ CN H B-81. CF₃ 6-F CN H B-82.CF₃ 6-CH₃ CN H B-83. CF₃ 6-OCH₃ CN H B-84. OCH₂F 3-F CN H B-85. OCH₂F3-CH₃ CN H B-86. OCH₂F 3-OCH₃ CN H B-87. OCH₂F 5-F CN H B-88. OCH₂F5-CH₃ CN H B-89. OCH₂F 5-OCH₃ CN H B-90. OCH₂F 6-F CN H B-91. OCH₂F6-CH₃ CN H B-92. OCH₂F 6-OCH₃ CN H B-93. OCHF₂ 3-F CN H B-94. OCHF₂3-CH₃ CN H B-95. OCHF₂ 3-OCH₃ CN H B-96. OCHF₂ 5-F CN H B-97. OCHF₂5-CH₃ CN H B-98. OCHF₂ 5-OCH₃ CN H B-99. OCHF₂ 6-F CN H B-100. OCHF₂6-CH₃ CN H B-101. OCHF₂ 6-OCH₃ CN H B-102. OCF₃ 3-F CN H B-103. OCF₃3-CH₃ CN H B-104. OCF₃ 3-OCH₃ CN H B-105. OCF₃ 5-F CN H B-106. OCF₃5-CH₃ CN H B-107. OCF₃ 5-OCH₃ CN H B-108. OCF₃ 6-F CN H B-109. OCF₃6-CH₃ CN H B-110. OCF₃ 6-OCH₃ CN H B-111. H H F H B-112. F H F H B-113.CH₃ H F H B-114. OCH₃ H F H B-115. CN H F H B-116. CH₂F H F H B-117.CHF₂ H F H B-118. CF₃ H F H B-119. OCH₂F H F H B-120. OCHF₂ H F H B-121.OCF₃ H F H B-122. H 3-F F H B-123. H 3-CH₃ F H B-124. H 3-OCH₃ F HB-125. H 5-F F H B-126. H 5-CH₃ F H B-127. H 5-OCH₃ F H B-128. H 6-F F HB-129. H 6-CH₃ F H B-130. H 6-OCH₃ F H B-131. F 3-F F H B-132. F 3-CH₃ FH B-133. F 3-OCH₃ F H B-134. F 5-F F H B-135. F 5-CH₃ F H B-136. F5-OCH₃ F H B-137. F 6-F F H B-138. F 6-CH₃ F H B-139. F 6-OCH₃ F HB-140. CH₃ 3-F F H B-141. CH₃ 3-CH₃ F H B-142. CH₃ 3-OCH₃ F H B-143. CH₃5-F F H B-144. CH₃ 5-CH₃ F H B-145. CH₃ 5-OCH₃ F H B-146. CH₃ 6-F F HB-147. CH₃ 6-CH₃ F H B-148. CH₃ 6-OCH₃ F H B-149. OCH₃ 3-F F H B-150.OCH₃ 3-CH₃ F H B-151. OCH₃ 3-OCH₃ F H B-152. OCH₃ 5-F F H B-153. OCH₃5-CH₃ F H B-154. OCH₃ 5-OCH₃ F H B-155. OCH₃ 6-F F H B-156. OCH₃ 6-CH₃ FH B-157. OCH₃ 6-OCH₃ F H B-158. CN 3-F F H B-159. CN 3-CH₃ F H B-160. CN3-OCH₃ F H B-161. CN 5-F F H B-162. CN 5-CH₃ F H B-163. CN 5-OCH₃ F HB-164. CN 6-F F H B-165. CN 6-CH₃ F H B-166. CN 6-OCH₃ F H B-167. CH₂F3-F F H B-168. CH₂F 3-CH₃ F H B-169. CH₂F 3-OCH₃ F H B-170. CH₂F 5-F F HB-171. CH₂F 5-CH₃ F H B-172. CH₂F 5-OCH₃ F H B-173. CH₂F 6-F F H B-174.CH₂F 6-CH₃ F H B-175. CH₂F 6-OCH₃ F H B-176. CHF₂ 3-F F H B-177. CHF₂3-CH₃ F H B-178. CHF₂ 3-OCH₃ F H B-179. CHF₂ 5-F F H B-180. CHF₂ 5-CH₃ FH B-181. CHF₂ 5-OCH₃ F H B-182. CHF₂ 6-F F H B-183. CHF₂ 6-CH₃ F HB-184. CHF₂ 6-OCH₃ F H B-185. CF₃ 3-F F H B-186. CF₃ 3-CH₃ F H B-187.CF₃ 3-OCH₃ F H B-188. CF₃ 5-F F H B-189. CF₃ 5-CH₃ F H B-190. CF₃ 5-OCH₃F H B-191. CF₃ 6-F F H B-192. CF₃ 6-CH₃ F H B-193. CF₃ 6-OCH₃ F H B-194.OCH₂F 3-F F H B-195. OCH₂F 3-CH₃ F H B-196. OCH₂F 3-OCH₃ F H B-197.OCH₂F 5-F F H B-198. OCH₂F 5-CH₃ F H B-199. OCH₂F 5-OCH₃ F H B-200.OCH₂F 6-F F H B-201. OCH₂F 6-CH₃ F H B-202. OCH₂F 6-OCH₃ F H B-203.OCHF₂ 3-F F H B-204. OCHF₂ 3-CH₃ F H B-205. OCHF₂ 3-OCH₃ F H B-206.OCHF₂ 5-F F H B-207. OCHF₂ 5-CH₃ F H B-208. OCHF₂ 5-OCH₃ F H B-209.OCHF₂ 6-F F H B-210. OCHF₂ 6-CH₃ F H B-211. OCHF₂ 6-OCH₃ F H B-212. OCF₃3-F F H B-213. OCF₃ 3-CH₃ F H B-214. OCF₃ 3-OCH₃ F H B-215. OCF₃ 5-F F HB-216. OCF₃ 5-CH₃ F H B-217. OCF₃ 5-OCH₃ F H B-218. OCF₃ 6-F F H B-219.OCF₃ 6-CH₃ F H B-220. OCF₃ 6-OCH₃ F H B-221. H H Cl H B-222. F H Cl HB-223. CH₃ H Cl H B-224. OCH₃ H Cl H B-225. CN H Cl H B-226. CH₂F H Cl HB-227. CHF₂ H Cl H B-228. CF₃ H Cl H B-229. OCH₂F H Cl H B-230. OCHF₂ HCl H B-231. OCF₃ H Cl H B-232. H 3-F Cl H B-233. H 3-CH₃ Cl H B-234. H3-OCH₃ Cl H B-235. H 5-F Cl H B-236. H 5-CH₃ Cl H B-237. H 5-OCH₃ Cl HB-238. H 6-F Cl H B-239. H 6-CH₃ Cl H B-240. H 6-OCH₃ Cl H B-241. F 3-FCl H B-242. F 3-CH₃ Cl H B-243. F 3-OCH₃ Cl H B-244. F 5-F Cl H B-245. F5-CH₃ Cl H B-246. F 5-OCH₃ Cl H B-247. F 6-F Cl H B-248. F 6-CH₃ Cl HB-249. F 6-OCH₃ Cl H B-250. CH₃ 3-F Cl H B-251. CH₃ 3-CH₃ Cl H B-252.CH₃ 3-OCH₃ Cl H B-253. CH₃ 5-F Cl H B-254. CH₃ 5-CH₃ Cl H B-255. CH₃5-OCH₃ Cl H B-256. CH₃ 6-F Cl H B-257. CH₃ 6-CH₃ Cl H B-258. CH₃ 6-OCH₃Cl H B-259. OCH₃ 3-F Cl H B-260. OCH₃ 3-CH₃ Cl H B-261. OCH₃ 3-OCH₃ Cl HB-262. OCH₃ 5-F Cl H B-263. OCH₃ 5-CH₃ Cl H B-264. OCH₃ 5-OCH₃ Cl HB-265. OCH₃ 6-F Cl H B-266. OCH₃ 6-CH₃ Cl H B-267. OCH₃ 6-OCH₃ Cl HB-268. CN 3-F Cl H B-269. CN 3-CH₃ Cl H B-270. CN 3-OCH₃ Cl H B-271. CN5-F Cl H B-272. CN 5-CH₃ Cl H B-273. CN 5-OCH₃ Cl H B-274. CN 6-F Cl HB-275. CN 6-CH₃ Cl H B-276. CN 6-OCH₃ Cl H B-277. CH₂F 3-F Cl H B-278.CH₂F 3-CH₃ Cl H B-279. CH₂F 3-OCH₃ Cl H B-280. CH₂F 5-F Cl H B-281. CH₂F5-CH₃ Cl H B-282. CH₂F 5-OCH₃ Cl H B-283. CH₂F 6-F Cl H B-284. CH₂F6-CH₃ Cl H B-285. CH₂F 6-OCH₃ Cl H B-286. CHF₂ 3-F Cl H B-287. CHF₂3-CH₃ Cl H B-288. CHF₂ 3-OCH₃ Cl H B-289. CHF₂ 5-F Cl H B-290. CHF₂5-CH₃ Cl H B-291. CHF₂ 5-OCH₃ Cl H B-292. CHF₂ 6-F Cl H B-293. CHF₂6-CH₃ Cl H B-294. CHF₂ 6-OCH₃ Cl H B-295. CF₃ 3-F Cl H B-296. CF₃ 3-CH₃Cl H B-297. CF₃ 3-OCH₃ Cl H B-298. CF₃ 5-F Cl H B-299. CF₃ 5-CH₃ Cl HB-300. CF₃ 5-OCH₃ Cl H B-301. CF₃ 6-F Cl H B-302. CF₃ 6-CH₃ Cl H B-303.CF₃ 6-OCH₃ Cl H B-304. OCH₂F 3-F Cl H B-305. OCH₂F 3-CH₃ Cl H B-306.OCH₂F 3-OCH₃ Cl H B-307. OCH₂F 5-F Cl H B-308. OCH₂F 5-CH₃ Cl H B-309.OCH₂F 5-OCH₃ Cl H B-310. OCH₂F 6-F Cl H B-311. OCH₂F 6-CH₃ Cl H B-312.OCH₂F 6-OCH₃ Cl H B-313. OCHF₂ 3-F Cl H B-314. OCHF₂ 3-CH₃ Cl H B-315.OCHF₂ 3-OCH₃ Cl H B-316. OCHF₂ 5-F Cl H B-317. OCHF₂ 5-CH₃ Cl H B-318.OCHF₂ 5-OCH₃ Cl H B-319. OCHF₂ 6-F Cl H B-320. OCHF₂ 6-CH₃ Cl H B-321.OCHF₂ 6-OCH₃ Cl H B-322. OCF₃ 3-F Cl H B-323. OCF₃ 3-CH₃ Cl H B-324.OCF₃ 3-OCH₃ Cl H B-325. OCF₃ 5-F Cl H B-326. OCF₃ 5-CH₃ Cl H B-327. OCF₃5-OCH₃ Cl H B-328. OCF₃ 6-F Cl H B-329. OCF₃ 6-CH₃ Cl H B-330. OCF₃6-OCH₃ Cl H B-331. H H CN F B-332. F H CN F B-333. CH₃ H CN F B-334.OCH₃ H CN F B-335. CN H CN F B-336. CH₂F H CN F B-337. CHF₂ H CN FB-338. CF₃ H CN F B-339. OCH₂F H CN F B-340. OCHF₂ H CN F B-341. OCF₃ HCN F B-342. H 3-F CN F B-343. H 3-CH₃ CN F B-344. H 3-OCH₃ CN F B-345. H5-F CN F B-346. H 5-CH₃ CN F B-347. H 5-OCH₃ CN F B-348. H 6-F CN FB-349. H 6-CH₃ CN F B-350. H 6-OCH₃ CN F B-351. F 3-F CN F B-352. F3-CH₃ CN F B-353. F 3-OCH₃ CN F B-354. F 5-F CN F B-355. F 5-CH₃ CN FB-356. F 5-OCH₃ CN F B-357. F 6-F CN F B-358. F 6-CH₃ CN F B-359. F6-OCH₃ CN F B-360. CH₃ 3-F CN F B-361. CH₃ 3-CH₃ CN F B-362. CH₃ 3-OCH₃CN F B-363. CH₃ 5-F CN F B-364. CH₃ 5-CH₃ CN F B-365. CH₃ 5-OCH₃ CN FB-366. CH₃ 6-F CN F B-367. CH₃ 6-CH₃ CN F B-368. CH₃ 6-OCH₃ CN F B-369.OCH₃ 3-F CN F B-370. OCH₃ 3-CH₃ CN F B-371. OCH₃ 3-OCH₃ CN F B-372. OCH₃5-F CN F B-373. OCH₃ 5-CH₃ CN F B-374. OCH₃ 5-OCH₃ CN F B-375. OCH₃ 6-FCN F B-376. OCH₃ 6-CH₃ CN F B-377. OCH₃ 6-OCH₃ CN F B-378. CN 3-F CN FB-379. CN 3-CH₃ CN F B-380. CN 3-OCH₃ CN F B-381. CN 5-F CN F B-382. CN5-CH₃ CN F B-383. CN 5-OCH₃ CN F B-384. CN 6-F CN F B-385. CN 6-CH₃ CN FB-386. CN 6-OCH₃ CN F B-387. CH₂F 3-F CN F B-388. CH₂F 3-CH₃ CN F B-389.CH₂F 3-OCH₃ CN F B-390. CH₂F 5-F CN F B-391. CH₂F 5-CH₃ CN F B-392. CH₂F5-OCH₃ CN F B-393. CH₂F 6-F CN F B-394. CH₂F 6-CH₃ CN F B-395. CH₂F6-OCH₃ CN F B-396. CHF₂ 3-F CN F B-397. CHF₂ 3-CH₃ CN F B-398. CHF₂3-OCH₃ CN F B-399. CHF₂ 5-F CN F B-400. CHF₂ 5-CH₃ CN F B-401. CHF₂5-OCH₃ CN F B-402. CHF₂ 6-F CN F B-403. CHF₂ 6-CH₃ CN F B-404. CHF₂6-OCH₃ CN F B-405. CF₃ 3-F CN F B-406. CF₃ 3-CH₃ CN F B-407. CF₃ 3-OCH₃CN F B-408. CF₃ 5-F CN F B-409. CF₃ 5-CH₃ CN F B-410. CF₃ 5-OCH₃ CN FB-411. CF₃ 6-F CN F B-412. CF₃ 6-CH₃ CN F B-413. CF₃ 6-OCH₃ CN F B-414.OCH₂F 3-F CN F B-415. OCH₂F 3-CH₃ CN F B-416. OCH₂F 3-OCH₃ CN F B-417.OCH₂F 5-F CN F B-418. OCH₂F 5-CH₃ CN F B-419. OCH₂F 5-OCH₃ CN F B-420.OCH₂F 6-F CN F B-421. OCH₂F 6-CH₃ CN F B-422. OCH₂F 6-OCH₃ CN F B-423.OCHF₂ 3-F CN F B-424. OCHF₂ 3-CH₃ CN F B-425. OCHF₂ 3-OCH₃ CN F B-426.OCHF₂ 5-F CN F B-427. OCHF₂ 5-CH₃ CN F B-428. OCHF₂ 5-OCH₃ CN F B-429.OCHF₂ 6-F CN F B-430. OCHF₂ 6-CH₃ CN F B-431. OCHF₂ 6-OCH₃ CN F B-432.OCF₃ 3-F CN F B-433. OCF₃ 3-CH₃ CN F B-434. OCF₃ 3-OCH₃ CN F B-435. OCF₃5-F CN F B-436. OCF₃ 5-CH₃ CN F B-437. OCF₃ 5-OCH₃ CN F B-438. OCF₃ 6-FCN F B-439. OCF₃ 6-CH₃ CN F B-440. OCF₃ 6-OCH₃ CN F B-441. H H F FB-442. F H F F B-443. CH₃ H F F B-444. OCH₃ H F F B-445. CN H F F B-446.CH₂F H F F B-447. CHF₂ H F F B-448. CF₃ H F F B-449. OCH₂F H F F B-450.OCHF₂ H F F B-451. OCF₃ H F F B-452. H 3-F F F B-453. H 3-CH₃ F F B-454.H 3-OCH₃ F F B-455. H 5-F F F B-456. H 5-CH₃ F F B-457. H 5-OCH₃ F FB-458. H 6-F F F B-459. H 6-CH₃ F F B-460. H 6-OCH₃ F F B-461. F 3-F F FB-462. F 3-CH₃ F F B-463. F 3-OCH₃ F F B-464. F 5-F F F B-465. F 5-CH₃ FF B-466. F 5-OCH₃ F F B-467. F 6-F F F B-468. F 6-CH₃ F F B-469. F6-OCH₃ F F B-470. CH₃ 3-F F F B-471. CH₃ 3-CH₃ F F B-472. CH₃ 3-OCH₃ F FB-473. CH₃ 5-F F F B-474. CH₃ 5-CH₃ F F B-475. CH₃ 5-OCH₃ F F B-476. CH₃6-F F F B-477. CH₃ 6-CH₃ F F B-478. CH₃ 6-OCH₃ F F B-479. OCH₃ 3-F F FB-480. OCH₃ 3-CH₃ F F B-481. OCH₃ 3-OCH₃ F F B-482. OCH₃ 5-F F F B-483.OCH₃ 5-CH₃ F F B-484. OCH₃ 5-OCH₃ F F B-485. OCH₃ 6-F F F B-486. OCH₃6-CH₃ F F B-487. OCH₃ 6-OCH₃ F F B-488. CN 3-F F F B-489. CN 3-CH₃ F FB-490. CN 3-OCH₃ F F B-491. CN 5-F F F B-492. CN 5-CH₃ F F B-493. CN5-OCH₃ F F B-494. CN 6-F F F B-495. CN 6-CH₃ F F B-496. CN 6-OCH₃ F FB-497. CH₂F 3-F F F B-498. CH₂F 3-CH₃ F F B-499. CH₂F 3-OCH₃ F F B-500.CH₂F 5-F F F B-501. CH₂F 5-CH₃ F F B-502. CH₂F 5-OCH₃ F F B-503. CH₂F6-F F F B-504. CH₂F 6-CH₃ F F B-505. CH₂F 6-OCH₃ F F B-506. CHF₂ 3-F F FB-507. CHF₂ 3-CH₃ F F B-508. CHF₂ 3-OCH₃ F F B-509. CHF₂ 5-F F F B-510.CHF₂ 5-CH₃ F F B-511. CHF₂ 5-OCH₃ F F B-512. CHF₂ 6-F F F B-513. CHF₂6-CH₃ F F B-514. CHF₂ 6-OCH₃ F F B-515. CF₃ 3-F F F B-516. CF₃ 3-CH₃ F FB-517. CF₃ 3-OCH₃ F F B-518. CF₃ 5-F F F B-519. CF₃ 5-CH₃ F F B-520. CF₃5-OCH₃ F F B-521. CF₃ 6-F F F B-522. CF₃ 6-CH₃ F F B-523. CF₃ 6-OCH₃ F FB-524. OCH₂F 3-F F F B-525. OCH₂F 3-CH₃ F F B-526. OCH₂F 3-OCH₃ F FB-527. OCH₂F 5-F F F B-528. OCH₂F 5-CH₃ F F B-529. OCH₂F 5-OCH₃ F FB-530. OCH₂F 6-F F F B-531. OCH₂F 6-CH₃ F F B-532. OCH₂F 6-OCH₃ F FB-533. OCHF₂ 3-F F F B-534. OCHF₂ 3-CH₃ F F B-535. OCHF₂ 3-OCH₃ F FB-536. OCHF₂ 5-F F F B-537. OCHF₂ 5-CH₃ F F B-538. OCHF₂ 5-OCH₃ F FB-539. OCHF₂ 6-F F F B-540. OCHF₂ 6-CH₃ F F B-541. OCHF₂ 6-OCH₃ F FB-542. OCF₃ 3-F F F B-543. OCF₃ 3-CH₃ F F B-544. OCF₃ 3-OCH₃ F F B-545.OCF₃ 5-F F F B-546. OCF₃ 5-CH₃ F F B-547. OCF₃ 5-OCH₃ F F B-548. OCF₃6-F F F B-549. OCF₃ 6-CH₃ F F B-550. OCF₃ 6-OCH₃ F F B-551. H H Cl FB-552. F H Cl F B-553. CH₃ H Cl F B-554. OCH₃ H Cl F B-555. CN H Cl FB-556. CH₂F H Cl F B-557. CHF₂ H Cl F B-558. CF₃ H Cl F B-559. OCH₂F HCl F B-560. OCHF₂ H Cl F B-561. OCF₃ H Cl F B-562. H 3-F Cl F B-563. H3-CH₃ Cl F B-564. H 3-OCH₃ Cl F B-565. H 5-F Cl F B-566. H 5-CH₃ Cl FB-567. H 5-OCH₃ Cl F B-568. H 6-F Cl F B-569. H 6-CH₃ Cl F B-570. H6-OCH₃ Cl F B-571. F 3-F Cl F B-572. F 3-CH₃ Cl F B-573. F 3-OCH₃ Cl FB-574. F 5-F Cl F B-575. F 5-CH₃ Cl F B-576. F 5-OCH₃ Cl F B-577. F 6-FCl F B-578. F 6-CH₃ Cl F B-579. F 6-OCH₃ Cl F B-580. CH₃ 3-F Cl F B-581.CH₃ 3-CH₃ Cl F B-582. CH₃ 3-OCH₃ Cl F B-583. CH₃ 5-F Cl F B-584. CH₃5-CH₃ Cl F B-585. CH₃ 5-OCH₃ Cl F B-586. CH₃ 6-F Cl F B-587. CH₃ 6-CH₃Cl F B-588. CH₃ 6-OCH₃ Cl F B-589. OCH₃ 3-F Cl F B-590. OCH₃ 3-CH₃ Cl FB-591. OCH₃ 3-OCH₃ Cl F B-592. OCH₃ 5-F Cl F B-593. OCH₃ 5-CH₃ Cl FB-594. OCH₃ 5-OCH₃ Cl F B-595. OCH₃ 6-F Cl F B-596. OCH₃ 6-CH₃ Cl FB-597. OCH₃ 6-OCH₃ Cl F B-598. CN 3-F Cl F B-599. CN 3-CH₃ Cl F B-600.CN 3-OCH₃ Cl F B-601. CN 5-F Cl F B-602. CN 5-CH₃ Cl F B-603. CN 5-OCH₃Cl F B-604. CN 6-F Cl F B-605. CN 6-CH₃ Cl F B-606. CN 6-OCH₃ Cl FB-607. CH₂F 3-F Cl F B-608. CH₂F 3-CH₃ Cl F B-609. CH₂F 3-OCH₃ Cl FB-610. CH₂F 5-F Cl F B-611. CH₂F 5-CH₃ Cl F B-612. CH₂F 5-OCH₃ Cl FB-613. CH₂F 6-F Cl F B-614. CH₂F 6-CH₃ Cl F B-615. CH₂F 6-OCH₃ Cl FB-616. CHF₂ 3-F Cl F B-617. CHF₂ 3-CH₃ Cl F B-618. CHF₂ 3-OCH₃ Cl FB-619. CHF₂ 5-F Cl F B-620. CHF₂ 5-CH₃ Cl F B-621. CHF₂ 5-OCH₃ Cl FB-622. CHF₂ 6-F Cl F B-623. CHF₂ 6-CH₃ Cl F B-624. CHF₂ 6-OCH₃ Cl FB-625. CF₃ 3-F Cl F B-626. CF₃ 3-CH₃ Cl F B-627. CF₃ 3-OCH₃ Cl F B-628.CF₃ 5-F Cl F B-629. CF₃ 5-CH₃ Cl F B-630. CF₃ 5-OCH₃ Cl F B-631. CF₃ 6-FCl F B-632. CF₃ 6-CH₃ Cl F B-633. CF₃ 6-OCH₃ Cl F B-634. OCH₂F 3-F Cl FB-635. OCH₂F 3-CH₃ Cl F B-636. OCH₂F 3-OCH₃ Cl F B-637. OCH₂F 5-F Cl FB-638. OCH₂F 5-CH₃ Cl F B-639. OCH₂F 5-OCH₃ Cl F B-640. OCH₂F 6-F Cl FB-641. OCH₂F 6-CH₃ Cl F B-642. OCH₂F 6-OCH₃ Cl F B-643. OCHF₂ 3-F Cl FB-644. OCHF₂ 3-CH₃ Cl F B-645. OCHF₂ 3-OCH₃ Cl F B-646. OCHF₂ 5-F Cl FB-647. OCHF₂ 5-CH₃ Cl F B-648. OCHF₂ 5-OCH₃ Cl F B-649. OCHF₂ 6-F Cl FB-650. OCHF₂ 6-CH₃ Cl F B-651. OCHF₂ 6-OCH₃ Cl F B-652. OCF₃ 3-F Cl FB-653. OCF₃ 3-CH₃ Cl F B-654. OCF₃ 3-OCH₃ Cl F B-655. OCF₃ 5-F Cl FB-656. OCF₃ 5-CH₃ Cl F B-657. OCF₃ 5-OCH₃ Cl F B-658. OCF₃ 6-F Cl FB-659. OCF₃ 6-CH₃ Cl F B-660. OCF₃ 6-OCH₃ Cl F

The positions (e.g. 3-/5-/6-) of R³ are relative to the 2- and4-positions of radicals R¹ and R² and to the 1-position of theattachment point of the ring to the SO₂ group.

The preferred compounds among the compounds I.1 to I.72 mentioned aboveare those of the formulae I.1 to I.6 and I.37 to I.42, and especiallycompounds of the formulae I.1 to I.6. Particularly preferred arecompounds of the formulae I.1 to I.3.

In a specific embodiment, the compounds I are selected from thecompounds specified in the examples, either as a free base or in form ofa pharmaceutically acceptable salt, an N-oxide or a stereoisomer or theracemate or any mixture of the steroisomers thereof.

The compounds I of the invention have a center of chirality in position3 of the 2-oxindole ring. The compounds of the invention may thereforebe in the form of a 1:1 mixture of enantiomers (racemate) or of anonracemic mixture of enantiomers in which one of the two enantiomers,either the enantiomer which rotates the plane of vibration of linearlypolarized light to the left (i.e. minus rotation) (hereinafter (−)enantiomer) or the enantiomer which rotates the plane of vibration oflinearly polarized light to the right (i.e. plus rotation) (hereinafter(+) enantiomer), is enriched, or of substantially enantiopure compounds,that is to say of substantially enantiopure (−) enantiomer or (+)enantiomer. Since the compounds of the invention have a single center ofasymmetry and no axis/plane of chirality, a nonracemic mixture can alsobe defined as a mixture of enantiomers in which either the R or the Senantiomer predominates. Substantially enantiopure compounds canaccordingly also be defined as substantially enantiopure R enantiomer orsubstantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of thepresent invention those compounds having an enantiomeric excess (ee; %ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably atleast 85% ee, more preferably at least 90% ee, even more preferably atleast 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention arein the form of substantially enantiopure compounds. Particularlypreferred compounds have an enantiomeric excess of at least 85% ee, morepreferably of at least 90% ee, even more preferably of at least 95% eeand in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixturesthereof, e.g. mixtures in which one enantiomer is present in enrichedform, but also to the racemates. The invention also relates to thepharmaceutically acceptable salts of the pure enantiomers of compoundsI, and the mixtures of enantiomers in the form of the pharmaceuticallyacceptable salts of compounds I.

Preferred embodiments of the invention are compounds of the formula I asdetailed above which are characterized in that they are in opticallyactive form, and the enantiomer of the relevant compound of the formulaI is the S-enantiomner, in the form of a free base, or apharmaceutically acceptable salt thereof.

Particularly preference is given to compounds of the general formula Iand their pharmaceutically acceptable salts as detailed above in whichthe corresponding S-enantiomer is present in an optical purity(enantiomeric excess, ee) of more than 50% ee, particularly preferablyof at least 80% ee, more preferably of at least 90% ee and even morepreferably of at least 95% ee and in particular of at least 98% ee.

Likewise preferred embodiments of the invention are compounds of thegeneral formula I as detailed above which are characterized in that theyare in optically inactive form, i.e. in the form of the racemate, or inthe form of a pharmaceutically acceptable salt of the racemate.

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The compounds of the invention can be prepared by using methodsdescribed in WO 2005/030755, WO 2006/005609 and the other referencesmentioned in the outset for synthesizing analogous compounds, and thepreparation is outlined by way of example in synthesis scheme 1. Thevariables in these synthetic schemes have the same meanings as informula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition ofmetallated heterocycles III onto the 3-keto group of the isatins II. Themetallated heterocycles, such as, for example, the correspondingGrignard (Mg) or organyllithium compound, can be obtained in anyconventional way from halogen or hydrocarbon compounds. Examples ofmethods are present in Houben-Weyl, Methoden der Organischen Chemie,vol. 13, 1-2, chapter on Mg and Li compounds. The isatins II are eithercommercially available or were prepared in analogy to methods describedin the literature (Advances in Heterocyclic Chemistry, A. R. Katritzkyand A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil.Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV can be converted into the compounds V whichhave a leaving group LG′ in position 3, where the leaving group LG′ is aconventional leaving group such as, for example, chlorine or bromide.The intermediate V with for example LG′=chlorine can be prepared bytreating the alcohol IV with thionyl chloride in the presence of a basesuch as, for example, pyridine, in a suitable solvent such as, forexample, dichloromethane.

The compounds V can subsequently be reacted with amines, such as, forexample, ammonia, in a substitution reaction to give the amines VI. Thecompounds VI can subsequently be converted by treatment with sulfonylchlorides VII after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in DMF into thesulfonylated product VIII. The sulfonyl chlorides VII employed caneither be purchased or be prepared by known processes (for example J.Med. Chem. 40, 1149 (1997)). The compounds VIII are then reacted withphenyl chloroformate in the presence of a base such as, for example,pyridine to give the corresponding phenyl carbamate IX.

The compounds of the invention of the general formula I which have aurea group in position 3 can be prepared as described in WO 2005/030755and WO 2006/005609, and shown in synthesis scheme 1, by two differentsequences: In the first variant, compound IX is first reacted with amineX, where appropriate at elevated temperature and with the addition ofauxiliary bases such as, for example, triethylamine ordiisopropylethylamine. PG is a protective group, typically Boc.Subsequent deprotection (for Boc typically treatment withtrifluoroacetic acid in dichloromethane) yields compound XII, which isthen reacted with the oxetan-3-one XIII to give compound I with X³ beinga bond. The latter reaction is carried out in the presence of a suitablereduction agent, e.g. boron-based reduction agent, typically a boronicester, such as sodium triacetoxyhydroborate, or cyanoborhydride. Forobtaining compounds wherein X³ is CH₂, oxetane-3-carbaldehyde optionallycarrying c substituents R¹⁰ is used instead of oxetanone XIII. Forobtaining compounds wherein X³ is CO, oxetane-3-carbonylchlorideoptionally carrying c substituents R¹⁰ is used instead of oxetanoneXIII.

In the second variant, compound IX is reacted with the amine XIV. Thereaction is generally carried out in the presence of a base, such astriethylamine or diisopropylethylamine.

The amines X can be either purchased or prepared by methods known fromthe literature. Compounds XIV wherein X³ is a bond can be prepared byreacting a compound X with oxetan-3-one carrying c substituents R¹⁰ inthe presence of a reduction agent such as sodium triacetoxyhydroborateor cyanoborhydride. For obtaining compounds XIV wherein X³ is CH₂,oxetane-3-carbaldehyde carrying c substituents R¹⁰ is used instead ofthe oxetan-3-one XIII. Analogously, for obtaining compounds XIV whereinX³ is C₂-C₄-alkylene, oxetane carrying in the 3-position a C₂-C₄-keto oraldehyde group (e.g. a group CH₂CHO, CH₂CH₂CHO, (CH₂)₃CHO, CH₂COCH₃,CH₂CH₂COCH₃ etc.) and carrying c substituents R¹⁰ is used instead of theoxetan-3-one XIII. Such oxetanes are either commercially available orcan be prepared by routine methods. For obtaining compounds wherein X³is CO, oxetane-3-carbonylchloride carrying c substituents R¹⁰ is usedinstead of the oxetan-3-one XIII.

If not indicated otherwise, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example a loweralcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone ormethyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the preparation methods are within routinetechniques.

Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporatedherein by reference in its entirety. Synthesis of the compounds of theinvention may be accomplished by methods analogous to those described inthe synthetic scheme described hereinabove and in specific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

The present invention moreover relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, the compounds according to the invention contain more of therespective isotope than this naturally occurs and thus is anyway presentin the compounds I.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one additional neutron than the normally abundantisotope of the respective atom. Deuterated compounds have been used inpharmaceutical research to investigate the in vivo metabolic fate of thecompounds by evaluation of the mechanism of action and metabolic pathwayof the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the designof safe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

Incorporation of a heavy atom, particularly substitution of deuteriumfor hydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases re-peatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising at least one compound of the general formula Iand/or an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof as detailed above, and a pharmaceutically acceptable carrier; orcomprising at least one compound I wherein at least one of the atoms hasbeen replaced by its stable, non-radioactive isotope, preferably whereinat least one hydrogen atom has been replaced by a deuterium atom, incombination with at least one pharmaceutically acceptable carrier and/orauxiliary substance. Suitable carriers depend inter alia on the dosageform of the composition and are known in principle to the skilledworker. Some suitable carriers are described hereinafter.

The present invention furthermore relates to a compound I as definedabove or an N-oxide, a stereoisomer or a pharmaceutically acceptablesalt thereof for use as a medicament. The present invention also relatesto a compound I as defined above or an N-oxide, a stereoisomer or apharmaceutically acceptable salt thereof for the treatment ofvasopressin-related diseases, especially of disorders which respond tothe modulation of the vasopressin receptor and in particular of the V1breceptor.

A further aspect of the present invention relates to the use ofcompounds of the formula I and/or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the manufacture of amedicament for the treatment and/or prophylaxis of vasopressin-relateddiseases, especially of disorders which respond to the modulation of thevasopressin receptor and in particular of the V1b receptor.

Vasopressin-related diseases are those in which the progress of thedisease is at least partly dependent on vasopressin, i.e. diseases whichshow an elevated vasopressin level which may contribute directly orindirectly to the pathological condition. In other words,vasopressin-related diseases are those which can be influenced bymodulating the vasopressin receptor, for example by administration of avasopressin receptor ligand (agonist, antagonist, partialantagonist/agonist, inverse agonist etc.).

Affective disorders have been related to excessive vasopressin function.Therefore, treatment with compounds targeting the vasopressin system,such as vasopressin antagonists are likely to benefit patients sufferingfrom affective disorders (see for example Surget A., Belzung C.,Involvement of vasopressin in affective disorders, Eur. J. Pharm. 2008,583, 340-349). Affective disorders (mood disorders) include depressivedisorders, anxiety disorders, obsessive-compulsive and relateddisorders, trauma and stressor-related disorders as well as bipolar andrelated disorders. V1b antagonist have been shown to have anti-drugabuse effects and reduce drug withdrawal effect (see e.g. Zhou Y., LeriF., Cummins E., Hoeschele M., Kreek M. J., Involvement of argininevasopressin and V1b receptor in heroin withdrawal and heroin seekingprecipitated by stress and by heroin. Neuropsychopharmacology, 2008, 33,226-236). Therefore, compound targeting the vasopressin system, such asvasopressin antagonists are thought to be effective for treatment ofSubstance-Related and Addictive Disorders. V1b receptors play a role ina range of emotional responses such as aggression. Attenuating V1breceptor function genetically or with antagonist reduces aggressivebehavior (Blanchard R. J., Griebel G., Farrokhi C., Markham C., Yang M.,Blanchard D. C., AVP V1b selective antagonist SSR149415 blocksaggressive behaviors in hamsters. Pharmacol. Biochem. Behav. 2005, 80,189-194; Wersinger S. R., Ginns E. I., O'Carroll A. M., Lolait S. J.,Young W. S., III, Vasopressin V1b receptor knockout reduces aggressivebehavior in male mice. Mol. Psychiatry, 2002, 7, 975-984). Therefore,attenuating V1b antagonists functioning is likely to reduce aggressionand agitation in disorders such as Alzheimer's disease andschizophrenia.

High cortisol levels have been correlated to reduced cognitiveperformance in elderly and AD (Alzheimer's disease) patients, and suchcorrelations are more pronounced in subjects carrying the APOs4 allele,which is a risk factor for AD (see for example Lee B. K., Glass T. A.,Wand G. S., McAtee M. J., Bandeen-Roche K., Bolla K. I., Schwartz B. S.,Apolipoprotein e genotype, cortisol, and cognitive function incommunity-dwelling older adults. Am. J. Psychiatry 2008, 165,1456-1464). Furthermore, increased plasma cortisol has been associatedwith more rapid disease progression in AD patients. Animal studies showan interaction between glucocorticoids and AD pathology, includingamyloid precursor protein and tau accumulation (see for example BudasG., Coughlan C. M., Seckl J. R., Breen K. C., The effect ofcorticosteroids on amyloid beta precursor protein/amyloid precursor-likeprotein expression and processing in vivo. Neurosci. Lett., 1999, 276,61-64). Cognitive performance can be impaired by stress or exposure tohigh doses of corticosterone in laboratory animals (for review seeRoozendaal B., Systems mediating acute glucocorticoid effects on memoryconsolidation and retrieval. Prog. Neuropsychopharmacol. Biol.Psychiatry, 2003, 27, 1213-1223). Therefore, lowering cortisol bytreatment with V1b antagonist may enhance cognition or prevent/slow downthe pathology or cognitive decline Alzheimer's Disease patients and inpatients with other cognitive impairment such as schizophrenia anddepression.

In a preferred embodiment, the present invention relates to the use ofcompounds of the invention of the formula I or of an N-oxide, astereoisomer or of pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from diabetes, insulin resistance, nocturnal enuresis,incontinence and diseases in which impairments of blood clotting occur,and/or for delaying micturition. The term “diabetes” means all types ofdiabetes, especially diabetes mellitus (including type I and especiallytype II), diabetes renalis and in particular diabetes insipidus. Thetypes of diabetes are preferably diabetes mellitus of type II (withinsulin resistance) or diabetes insipidus.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or of pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from hypertension, pulmonary hypertension, heartfailure, myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, impairments of the renal system, edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia,Schwartz-Bartter syndrome, impairments of the gastrointestinal tract,gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers,emesis, emesis occurring during chemotherapy, and travel sickness.

The compounds of the invention of the formula I or their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can also be used for the treatment ofvarious vasopressin-related complaints which have central nervous causesor alterations in the HPA axis (hypothalamic pituitary adrenal axis),for example for affective disorders such as depressive disorders,anxiety disorders, obsessive-compulsive and related disorders, traumaand stressor-related disorders, and bipolar and related disorders.Depressive disorders include for example dysthymic disorders, majordepression, seasonal depression, treatment-resistant depressiondisorders, disruptive mood dysregulation disorder, premenstrualdysphoric disorder, substance/medication-induced depressive disorder,depressive disorder due to another medical condition, bipolar disorders,or childhood onset mood disorders. Anxiety disorders include for examplephobias, specific phobias, general anxiety disorders, panic disorders,drug withdrawal-induced anxiety disorders, separation anxiety disorder,selective mutism, social anxiety disorder, agoraphobia,substance/medication-induced anxiety disorder and anxiety disorder dueto another medical condition. Obsessive-compulsive and related disordersinclude for example obsessive-compulsive disorder, body dysmorphicdisorder, hoarding disorder, trichotillomania, excoriation disorder,substance/medication-induced obsessive-compulsive and related disorderand other specified obsessive-compulsive and related disorders. Traumaand stressor-related disorders include for example reactive attachmentdisorder, disinhibited social engagement disorder, post traumatic stressdisorder, acute stress disorder, adjustment disorder and other specifiedtrauma- and stressor-related disorders. Bipolar and related disordersinclude for example bipolar I disorder, bipolar II disorder, cyclothymicdisorder, substance/medication-induced bipolar and related disorder,bipolar and related disorder due to another medical condition andunspecified bipolar and related disorder.

Vasopressin-related complaints which have central nervous causes oralterations in the HPA axis are further cognitive disorders such asAlzheimer's disease, MCI (Mild Cognitive Impairment) and CIAS (CognitiveImpairment Associated with Schizophrenia).

The compounds of the invention of the formula I and their N-oxides, astereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof anxiety disorders and stress-dependent anxiety disorders, such as,for example, generalized anxiety disorders, phobias, specific phobias,post-traumatic anxiety disorders, panic anxiety disorders,obsessive-compulsive anxiety disorders, acute stress-dependent anxietydisorders, drug withdrawal-induced anxiety disorders, separation anxietydisorder, selective mutism, social anxiety disorder, agoraphobia,substance/medication-induced anxiety disorder and anxiety disorder dueto another medical condition and social phobia. The compounds of theinvention of the formula I and their N-oxides, a stereoisomers orpharmaceutically acceptable salts or the pharmaceutical composition ofthe invention can likewise be employed for the treatment ofobsessive-compulsive and related disorders, including, for example,obsessive-compulsive disorder, body dysmorphic disorder, hoardingdisorder, trichotillomania, excoriation disorder,substance/medication-induced obsessive-compulsive and related disorderand other specified obsessive-compulsive and related disorders. Thecompounds of the invention of the formula I and their N-oxides, astereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof trauma and stressor-related disorders, including, for example,reactive attachment disorder, disinhibited social engagement disorder,post traumatic stress disorder, acute stress disorder, adjustmentdisorder and other specified trauma- and stressor-related disorders.

The compounds of the invention of the formula I and their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentand/or prophylaxis of social impairment, such as autism or socialimpairment related with schizophrenia.

The compounds of the invention of the formula I and their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentand/or prophylaxis of increased aggression in conditions such asAlzheimer's disease and schizophrenia.

The compounds of the invention can furthermore also be employed for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

Accordingly, a further preferred embodiment of the present inventionrelates to the use of compounds of the invention of the formula I or ofan N-oxide, a stereoisomer or pharmaceutically acceptable salts thereoffor the manufacture of a medicament for the treatment of affectivedisorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of anxiety disordersand/or stress-dependent anxiety disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of memory impairmentsand/or Alzheimer's disease.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of Cushing's syndrome orother stress-dependent diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of sleep disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of depressive disorders.In the case of depressive disorders, specific mention is to be made ofchildhood onset mood disorders, i.e. depressive moods having their onsetin childhood, but also of major depression, seasonal depression, bipolarand related disorders, dysthymic disorders, disruptive mooddysregulation disorder, premenstrual dysphoric disorder,substance/medication-induced depressive disorder, and depressivedisorder due to another medical condition, and especially of majordepression and seasonal depression as well as of the depressive phasesof bipolar disorders. Bipolar and related disorders include for examplebipolar I disorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorder, bipolar andrelated disorder due to another medical condition and unspecifiedbipolar and related disorder. The invention also relates to compounds ofthe formula I or N-oxides, stereoisomers or pharmaceutically acceptablesalts thereof for the manufacture of a medicament for the treatment oftreatment-resistant depression disorders and for the use in an add-ontherapy of depressive disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of vasomotor symptomsand/or thermoregulatory dysfunctions such as, for example, the hot flushsymptom.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis of drugor pharmaceutical dependencies and/or dependencies mediated by otherfactors, for the treatment of drug-use disorders, for the treatmentand/or prophylaxis of stress caused by withdrawal of one or more factorsmediating the dependence and/or for the treatment and/or prophylaxis ofstress-induced relapses into drug or pharmaceutical dependencies and/ordependencies mediated by other factors. To be more precise, the presentinvention relates to the use of compounds of the invention of theformula I or of an N-oxide, a stereoisomer or pharmaceuticallyacceptable salts thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of substance-related and addictivedisorders such as substance use disorder, substance-induced disorder,alcohol use disorder, alcohol intoxication, alcohol withdrawal,unspecified alcohol-related disorder, caffeine intoxication, caffeinewithdrawal, unspecified caffeine disorder, cannabis use disorder,cannabis withdrawal, unspecified cannabis-related disorder,phencyclidine use disorder, other hallucinogen use disorders,phencyclidine intoxication, other hallucinogen disorders, hallucinogenpersisting perception disorder, unspecified phencyclidine disorder,inhalant use disorder, inhalant intoxication, opioid use disorder,opioid withdrawal, sedative, hypnotic or anxiolytic use disorder,sedative, hypnotic or anxiolytic withdrawal, stimulant use disorder,stimulant intoxication, stimulant withdrawal, tobacco use disorder,tobacco withdrawal, unspecified tobacco-related disorder, other (orunknown) substance use disorders, other (or unknown) substanceintoxication, other (or unknown) substance withdrawal, other (orunknown) substance related disorder and gambling disorder.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofschizophrenia and/or psychosis.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofpain, e.g. acute or chronic pain, preferably chronic pain, especiallyneuropathic pain. Chronic pain may be a complex regional pain syndrome,pain arising from peripheral neuropathies, post-operative pain, chronicfatigue syndrome pain, tension-type headache, pain arising frommechanical nerve injury and severe pain associated with diseases such ascancer, metabolic disease, neurotropic viral disease, neurotoxicity,inflammation, multiple sclerosis or any pain arising as a consequence ofor associated with stress or depressive illness.

A further aspect of the invention relates to a compound I orpharmaceutically acceptable salts thereof for use as a medicament, andto a compound I or an N-oxide, a stereoisomer or pharmaceuticallyacceptable salts thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of the above-defined diseases.

A further aspect of the invention relates to a method for the treatmentand/or prophylaxis of vasopressin-related diseases, in which aneffective amount of at least one compound of the invention of theformula I or of an N-oxide, a stereoisomer or of at least onepharmaceutically acceptable salt thereof or of a pharmaceuticalcomposition of the invention is administered to a patient.

Concerning the definition of vasopressin-related diseases, reference ismade to the above statements.

In a preferred embodiment of the invention, the method of the inventionserves for the treatment and/or prophylaxis of disorders selected fromdiabetes, insulin resistance, nocturnal enuresis, incontinence anddiseases in which impairments of blood clotting occur, and/or fordelaying micturition. Concerning the definition of diabetes, referenceis made to the above statements.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of disorders selected fromhypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplasty), ischemias of the heart, impairmentsof the renal system, edemas, renal vasospasm, necrosis of the renalcortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome,impairments of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurringduring chemotherapy, and travel sickness.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of affective disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of anxiety disorders and/orstress-dependent anxiety disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of memory impairments and/orAlzheimer's disease.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of psychoses and/or psychoticdisorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of Cushing's syndrome.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of sleep disorders in a patient.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of depressive disorders. In thecase of depressive disorders, specific mention is to be made of majordepression, seasonal depression, bipolar and related disorders,dysthymic disorders, childhood onset mood disorders, i.e. depressivemoods having their onset in childhood, disruptive mood dysregulationdisorder, premenstrual dysphoric disorder, substance/medication-induceddepressive disorder, and depressive disorder due to another medicalcondition, and especially of major depression and seasonal depression aswell as of the depressive phases of bipolar disorders. Bipolar andrelated disorders include for example bipolar I disorder, bipolar IIdisorder, cyclothymic disorder, substance/medication-induced bipolar andrelated disorder, bipolar and related disorder due to another medicalcondition and unspecified bipolar and related disorder. The method ofthe invention also serves for the treatment of treatment-resistantdepression disorders and as an add-on therapy of depressive disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of vasomotor symptoms and/orthermoregulatory dysfunctions, such as, for example, the hot flushsymptom.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of drug or pharmaceuticaldependencies and/or dependencies mediated by other factors, for thetreatment of drug-use disorders, for the treatment and/or prophylaxis ofstress caused by withdrawal of one or more factors mediating thedependence, and/or for the treatment and/or prophylaxis ofstress-induced relapses into drug or pharmaceutical dependencies and/ordependencies mediated by other factors. To be more precise, the methodof the invention serves for the treatment and/or prophylaxis ofsubstance-related and addictive disorders such as substance usedisorder, substance-induced disorder, alcohol use disorder, alcoholintoxication, alcohol withdrawal, unspecified alcohol-related disorder,caffeine intoxication, caffeine withdrawal, unspecified caffeinedisorder, cannabis use disorder, cannabis withdrawal, unspecifiedcannabis-related disorder, phencyclidine use disorder, otherhallucinogen use disorders, phencyclidine intoxication, otherhallucinogen disorders, hallucinogen persisting perception disorder,unspecified phencyclidine disorder, inhalant use disorder, inhalantintoxication, opioid use disorder, opioid withdrawal, sedative, hypnoticor anxiolytic use disorder, sedative, hypnotic or anxiolytic withdrawal,stimulant use disorder, stimulant intoxication, stimulant withdrawal,tobacco use disorder, tobacco withdrawal, unspecified tobacco-relateddisorder, other (or unknown) substance use disorders, other (or unknown)substance intoxication, other (or unknown) substance withdrawal, other(or unknown) substance related disorder and gambling disorder.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of schizophrenia and/or psychosis.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of pain, e.g. acute or chronicpain, preferably chronic pain, especially neuropathic pain.

The patient to be treated prophylactically or therapeutically with themethod of the invention is preferably a mammal, for example a human or anonhuman mammal or a nonhuman transgenic mammal. Specifically it is ahuman.

The compounds of the general formula I and their pharmaceuticallyacceptable salts as detailed above can be prepared by a skilled workerwith knowledge of the technical teaching of the invention inimplementing and/or in analogous implementation of process steps knownper se.

The compounds I and/or their pharmaceutically acceptable salts, N-oxidesand their stereoisomers are distinguished by having a selectivity forthe vasopressin V1b receptor subtype vis-à-vis at least one of theclosely related vasopressin/oxytocin receptor subtypes (for examplevasopressin V1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I and/or theirpharmaceutically acceptable salts, N-oxides and a stereoisomers aredistinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (RS Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in the treatment orprophylaxis of various vasopressin-related diseases. In addition, animproved metabolic stability may lead to an increased bioavailabilityafter oral administration, because the compound is subject, afterabsorption in the intestine, to less metabolic degradation in the liver(so-called first pass effect). An increased oral bioavailability may,owing to an increased concentration (active level) of the compound, leadto a better activity of the compound after oral administration.

The compounds of the invention are effective after administration byvarious routes. Possible examples are intravenous, intramuscular,subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal,rectal, sublingual, buccal or oral administration, and administration isfrequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound I of the invention and/or anN-oxide, a stereoisomer and/or a pharmaceutically acceptable saltthereof and suitable pharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration and are known in principle to theskilled worker.

The compounds of the invention of the formula I, their N-oxides,steroisomers or optionally suitable salts of these compounds can be usedto produce pharmaceutical compositions for oral, sublingual, buccal,subcutaneous, intramuscular, intravenous, topical, intratracheal,intranasal, transdermal, vaginal or rectal administration, and beadministered to animals or humans in uniform administration forms, mixedwith conventional pharmaceutical carriers, for the prophylaxis ortreatment of the above disorders or diseases.

The suitable administration forms (dose units) include forms for oraladministration such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active ingredient can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered once to 5 times a day, sothat a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the activeingredient is mixed with a solid pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display asustained or delayed activity and to release a predetermined amount ofthe active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may contain active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloringsubstance.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositorieswhich are prepared with binders which melt at rectal temperature, forexample cocoa butter or polyethylene glycols. Parenteral administrationis effected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds ofthe invention, comprise other active ingredients which may be beneficialfor the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active ingredients are presenttogether, where at least one of these is a compound I of the invention,or salt thereof.

The invention is explained in more detail below by means of examples,but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various syntheticroutes. The methods mentioned, as described accordingly in synthesisscheme 1, are explained in greater detail merely by way of example usingthe given examples without being exclusively restricted to synthesisroute 1 or analogous methods.

EXPERIMENTAL SECTION

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxide or d-chloroform on a 600 MHz NMR instrument (BrukerAVANCE), or by mass spectrometry, generally recorded via HPLC-MS in afast gradient on C18-material (electrospray-ionisation (ESI) mode), ormelting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), doublet (d), triplet (t), quartet (q), quintet (quint.), multiplet(m), doublet of doublets (dd), doublet of doublet of doublets (ddd),doublet of triplets (dt), triplet of doublets (td), triplet of triplets(tt) or quartet of doublets (qd). See also below abbreviations.

Abbreviations used:

THF: Tetrahydrofuran

DMSO: Dimethyl sulfoxide

TFA: Trifluoroacetic acid

p: pseudo (for example pt pseudo triplet)

b or br.: broad (for example bs broad singlet)

sym. symmetric

s: singlet

d: doublet

t: triplet

m: multiplet

dd: doublet of doublets

ddd doublet of doublet of doublets

dt: doublet of triplets

td triplet of doublets

tt: triplet of triplets

qd quartet of doublets

I. Preparation of the Starting Compounds a.) Synthesis of1-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine (trifluoroacetic acidsalt) a.1) Synthesis of tert-butyl4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate

In a 100 ml round-bottom flask 2 g (7.42 mmol) of1-boc-4-(piperidin-4-yl)-piperazine and 1.07 g (14.85 mmol) of3-oxetanone were dissolved in 30 ml of dichloromethane. 3.16 g (22.27mmol) of sodium sulfate were added and the reaction was stirred for 10min. Subsequently, 2.203 g (10.39 mmol) of sodium triacetoxyborohydridewere added and the reaction was stirred for 5 min. pH was adjusted to5-6 with acetic acid and the reaction was stirred over night. Then, 50ml of water were added and the resulting two phases were separated. Theorganic phase was washed twice with water dried over MgSO₄, filtered andevaporated. The resulting solid was digested in methyl-tert-butyl ether,filtered off, washed with 10 ml of methyl-tert-butyl ether and dried.Flash chromatography (silica gel/gradient from 0 to 20% methanol indichloromethane) yielded 650 mg of the title compound as a yellowishsolid.

a.2) Synthesis of 1-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine(trifluoroacetic acid salt)

In a 100 ml round-bottom flask 1.63 g (5.01 mmol) of tert-butyl4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate weredissolved in 5 ml of dichloromethane. 3 ml (38.9 mmol) oftrifluoroacetic acid were added and the reaction was stirred for 30 min.The solution was concentrated and digested in 40 ml of methyl-tert-butylether. The solid was filtered and washed with 20 ml of methyl-tert-butylether to yield 2.79 of the title compound as a white solid.

b.) Synthesis of 1-(oxetan-3-yl)-4-(piperidin-4-yl)piperazine,(trifluoroacetic acid salt)

The compound was synthesized in analogy to a.), using however1-boc-4-(piperazin-4-yl)-piperidine as starting amine compound andNaBH₃CN/ZnCl as reduction agent.

c) Synthesis of 1-(oxetan-3-yl)-4,4′-bipiperidine c.1) Synthesis ofbenzyl 1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxylate

The compound was synthesized in analogy to a), using howeverbenzyl[4,4′-bipieridine]-1-carboxylate as starting amine compound.

c.2) Synthesis of 1-(oxetan-3-yl)-4,4′-bipiperidine

520 mg (1.45 mmol) of benzyl1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxylate was dissolved in 30ml methanol and hydrogenated in the H-cube® flow hydrogenator using a 10mol % Pd (C) cartridge at a flow rate of 1 ml/min. The solvent wasremoved in vacuo providing 372 mg of the title compound which was usedwithout further purification.

II. Preparation of the Compounds of the Formula I

Enantiomers of the compounds I were prepared by using enantiomericallypure starting compounds.

Example 1(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

Route A

In a 100 ml 3-necked flask, 100 mg (0.163 mmol) of(S)-phenyl(5-cyano-1-((2,4-dimethoxyphenyl)-sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-carbamatewas stirred in THF for 5 min. 111 mg (0.195 mmol) of1-(1-(oxetan-3-yl)piperidin-4-yl)-piperazine (used as trifluoroaceticacid salt) and 82 mg (0.814 mmol) of triethylamine were added and thereaction was stirred over night at room temperature. The solvent wasremoved, dichloromethane was added and the solution was extracted withwater. The organic phase was washed with aqueous Na₂CO₃, dried overMgSO₄ and the solvent was removed. The resulting crude product wassubjected to flash chromatography (silica gel/dichloromethane:methanol=90:10) to yield 98.2 mg (81%) of the title compound.

Route B B. 1) (S)-tert-butyl4-(4-((5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)piperazin-1-yl)piperidine-1-carboxylate

The compound was synthesized in analogy to Route A) using4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine as amine compound.

B. 2)(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(piperidin-4-yl)piperazine-1-carboxamide

To a solution of 2.53 g (3.20 mmol) of (S)-tert-butyl4-(4-((5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)piperazin-1-yl)piperidine-1-carboxylatein DCM (35 ml) was added 2.5 mL trifluoroacetic acid (32.4 mmol) and thereaction mixture was stirred overnight. The solvent was removed in vacuoand the residue was taken up in water/EtOAc (70 ml/70 ml). Afterneutralization with sat. aqueous NaHCO3

solution (20 ml), the organic phase was separated and the aqueous phaseextracted with EtOAc. The combined organic layers werde washed withbrine and dried (MgSO4). Purification by flash chromatography (silica,DCM/MeOH gradient 0-100% MeOH) provided 1 g (36%) of the title compoundas colorless solid.

B.3)(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

In a 100 ml 3-necked flask, 100 mg (0.145 mmol) of(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(piperidin-4-yl)-piperazine-1-carboxamidewere stirred in 4 ml of dichloromethane. 10.45 mg (0.145 mmol) ofoxetan-3-one dissolved in 2 ml of dichloromethane were added and themixture was stirred for 5 min. 30.7 mg of Na₂SO₄ were added and themixture was stirred for another 5 min. 17.41 mg of acetic acid wereadded and the reaction was stirred for another 30 min. 46.1 mg (0.217mmol) of sodium triacetoxyhydroborate were added and the reaction wasstirred overnight. 1 ml of 2N NaOH and then 7 ml of water were added andthe mixture was extracted thrice with ethylacetate and water. Theorganic phase was died over MgSO₄ and the solvent was removed. Theresulting crude product was subjected to flash chromatography (silicagel/gradient from 0 to 5% methanol in dichloromethane) to yield 26.4 mg(24.4%) of the title compound.

ESI-MS [M+H⁺]=746.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H),7.86 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.73 (m, 1H), 7.69 (s, 1H), 7.68(d, 1H), 7.04-7.02 (m, 1H), 6.70-6.66 (m, 2H), 4.51-4.49 (m, 2H),4.39-4.37 (m, 2H), 4.19-4.10 (m, 2H), 3.85 (s, 3H), 3.44 (s, 3H),3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.36-2.35 (m, 4H),2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.06 (t, 3H).

Example 2(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-61 of Table A)

The compound was prepared in analogy to route B of example 1.

ESI-MS [M+H⁺]=704.3;

¹H-NMR (600 MHz DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H), 7.87(d, 1H), 7.83 (m, 1H), 7.74-7.72 (m, 1H), 7.70 (s, 1H), 7.68 (d, 1H),7.04-7.02 (m, 1H), 6.69-6.66 (m, 2H), 4.52-4.49 (m, 2H), 4.40-4.38 (m,2H), 4.21-4.11 (m, 2H), 3.85 (s, 3H), 3.84-3.79 (m, 2H), 3.43 (s, 3H),3.34 (m, 1H), 2.66-2.56 (m, 2H), 2.47-2.15 (m, 9H), 1.65-1.58 (m, 2H),1.20-1.10 (m, 2H), 1.08 (t, 3H).

Example 3N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are asdefined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 ofTable A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.98-7.94 (m,3H), 7.86 (d, 1H), 7.82-7.81 (m, 1H), 7.73 (s, 1H), 7.61 (d, 1H),7.16-7.13 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 4.10-4.06 (m, 1H), 4.02-3.97 (m, 1H), 3.84 (s, 3H), 3.34-3.28 (m,1H), 3.17 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H),1.71-1.67 (m, 4H), 1.41-1.35 (m, 2H), 0.98 (t, 3H).

Example 4N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are asdefined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-1 ofTable A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=686.1;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.06-8.04 (m,2H), 7.99-7.97 (m, 1H), 7.87 (d, 1H), 7.84-7.82 (m, 1H), 7.79-7.77 (m,1H), 7.75 (s, 1H), 7.66-7.62 (m, 3H), 7.09-7.07 (m, 1H), 4.52-4.49 (m,2H), 4.41-4.37 (m, 2H), 4.11-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.34-3.28(m, 1H), 3.28 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m,1H), 1.74-1.67 (m, 4H), 1.44-1.35 (m, 2H), 0.96 (t, 3H).

Example 5(S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-14 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=711.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.18-8.13 (m, 5H), 8.08-8.06 (m,1H), 7.92 (d, 1H), 7.85-7.84 (m, 1H), 7.77 (s, 1H), 7.60 (d, 1H),7.13-7.10 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.11-4.07 (m,2H), 3.34-3.30 (m, 1H), 3.09 (m, 4H), 2.71-2.69 (m, 2H), 2.32 (m, 4H),2.19-2.17 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.37 (m, 2H), 1.05 (t, 3H).

Example 6(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-29 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=734.0;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.99-7.97 (m,1H), 7.94-7.88 (m, 2H), 7.84-7.83 (m, 1H), 7.71 (s, 1H), 7.62-7.61 (m,1H), 7.10-7.07 (m, 1H), 7.06-7.04 (m, 1H), 6.97-6.95 (m, 1H), 4.51-4.49(m, 2H), 4.39-4.37 (m, 2H), 4.14-4.08 (m, 2H), 3.85 (s, 3H), 3.34-3.29(m, 1H), 3.16-3.13 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.18-2.14(m, 1H), 1.71-1.65 (m, 4H), 1.43-1.35 (m, 2H), 1.03 (t, 3H).

Example 7N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are asdefined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-2083 ofTable A) The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.3

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.17-8.14 (m, 1H), 7.89 (d, 1H),7.82-7.81 (m, 1H), 7.72-7.69 (m, 3H), 7.06-7.04 (m, 1H), 6.71-6.68 (m,2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.11 (m, 2H), 3.86 (s,3H), 3.50 (s, 3H), 3.34-3.29 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H),2.34 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.40-1.34 (m, 2H),1.08 (t, 3H)

Example 7A(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-2083 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.87 (d, 1H),7.82-7.81 (m, 1H), 7.71-7.69 (m, 3H), 7.06-7.04 (m, 1H), 6.71-6.68 (m,2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.11 (m, 2H), 3.86 (s,3H), 3.51 (s, 3H), 3.35-3.30 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H),2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H),1.08 (t, 3H).

Example 8(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-270 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.0;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H),7.85-7.83 (m, 2H), 7.72-7.70 (m, 2H), 7.67-7.66 (m, 1H), 7.08-7.05 (m,1H), 6.90 (d, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.09 (m,2H), 3.95 (s, 3H), 3.51 (s, 3H), 3.34-3.28 (m, 1H), 3.19 (m, 4H),2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H),1.41-1.35 (m, 2H), 1.06 (t, 3H)

Example 9(S)—N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-2757 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=757.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.12 (m, 1H), 7.87 (d, 1H),7.66-7.62 (m, 3H), 7.37-7.34 (m, 1H), 7.01-6.99 (m, 1H), 6.70-6.66 (m,2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.21-4.13 (m, 2H), 3.86 (s,3H), 3.48 (s, 3H), 3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.70-2.69 (m, 2H),2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H),1.10 (t, 3H).

Example 10(S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-1409 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=755.5;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.12-8.11 (m, 1H), 7.88 (d, 1H),7.69 (d, 1H), 7.63 (s, 1H), 7.58-7.56 (m, 1H), 7.39-7.37 (m, 2H),6.99-6.97 (m, 1H), 6.70-6.66 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 4.22-4.12 (m, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 3.34-3.28 (m, 1H),3.21 (m, 4H), 2.71-2.69 (m, 2H), 2.36 (m, 4H), 2.18-2.15 (m, 1H),1.71-1.67 (m, 4H), 1.41-1.35 (m, 2H), 1.11 (t, 3H).

Example 11(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.3, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-61 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=745.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.11 (m, 1H), 7.88-7.87 (m,2H), 7.83-7.80 (m, 1H), 7.72-7.71 (m, 1H), 7.68-7.64 (m, 2H), 7.04-7.00(m, 1H), 6.70-6.68 (m, 1H), 6.66 (d, 1H), 4.52 (m, 2H), 4.41 (m, 2H),4.21-4.11 (m, 2H), 3.85 (s, 3H), 3.83 (m, 2H), 3.48 (s, 3H), 3.35 (m,1H), 2.71 (m, 2H), 2.57 (m, 2H), 1.70-1.52 (m, 6H), 1.17 (m, 3H), 1.07(t, 3H), 1.02 (m, 1H), 0.93-0.90 (m, 2H).

Example 12(S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-14 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=711.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.17-8.12 (m, 5H), 8.07-8.05 (m,1H), 7.93 (d, 1H), 7.85-7.83 (m, 1H), 7.74 (s, 1H), 7.60 (m, 1H),7.13-7.10 (m, 1H), 4.52-4.49 (m, 2H), 4.41-4.39 (m, 2H), 4.12-4.08 (m,2H), 3.72-3.63 (m, 2H), 3.38-3.32 (m, 1H), 2.58-2.56 (m, 2H), 2.46-2.23(m, 9H), 1.65-1.59 (m, 2H), 1.14-1.10 (m, 2H), 1.06 (t, 3H).

Example 13(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-13 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.97-7.93 (m,3H), 7.87 (d, 1H), 7.82-7.80 (m, 1H), 7.73 (s, 1H), 7.62 (d, 1H),7.15-7.13 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.40-4.38 (m,2H), 4.12-4.07 (m, 1H), 4.04-3.99 (m, 1H), 3.84 (s, 3H), 3.77 (m, 2H),3.34 (m, 1H), 2.61 (m, 2H), 2.47-2.22 (m, 9H), 1.65-1.60 (m, 2H),1.17-1.12 (m, 2H), 1.00 (t, 3H).

Example 14(S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-1409 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=756.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.87 (d, 1H),7.71-7.69 (m, 1H), 7.65 (s, 1H), 7.57-7.56 (m, 1H), 7.38-7.36 (m, 2H),6.99-6.97 (m, 1H), 6.69-6.68 (m, 1H), 6.66 (d, 1H), 4.52-4.50 (m, 2H),4.40-4.38 (m, 2H), 4.22-4.15 (m, 2H), 3.85 (m, 5H), 3.44 (s, 3H), 3.34(m, 1H), 2.62 (m, 3H), 2.52-2.22 (m, 8H), 1.63 (m, 2H), 1.16 (m, 2H),1.13 (t, 3H).

Example 15N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are asdefined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 ofTable A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.91-7.87 (m,2H), 7.81-7.80 (m, 1H), 7.75-7.74 (m, 1H), 7.71-7.68 (m, 2H), 7.05-7.04(m, 1H), 6.71-6.70 (m, 1H), 6.68 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37(m, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H), 3.35-3.29 (m, 1H),3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H),1.74-1.66 (m, 4H), 1.46-1.37 (m, 2H).

Example 16N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(Compound of formula I.5, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are asdefined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to rowA-61 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90-7.87 (m,2H), 7.81-7.79 (m, 1H), 7.73-7.68 (m, 3H), 7.05-7.03 (m, 1H), 6.70-6.67(m, 2H), 4.52-4.49 (m, 2H), 4.40-4.38 (m, 2H), 3.86 (s, 3H), 3.83-3.81(m, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.34 (m, 1H), 2.64-2.61 (m, 2H),2.50-2.23 (m, 9H), 1.61 (m, 2H), 1.16 (m, 2H).

Example 17N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 47 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

The compound was prepared in analogy to route B of example 1.

ESI-MS [M+H⁺]=758.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.88-7.87 (m,2H), 7.83-7.81 (m, 1H), 7.73-7.71 (m, 1H), 7.68 (d, 1H), 7.66 (m, 1H),7.03-7.01 (m, 1H), 6.67-6.68 (m, 1H), 6.66-6.65 (m, 1H), 4.56-4.54 (m,1H), 4.51-4.49 (m, 1H), 4.34-4.31 (m, 2H), 4.19-4.10 (m, 2H), 3.85 (s,3H), 3.81-3.79 (m, 1H), 3.66 (m, 2H), 3.53 (m, 5H), 2.71 (m, 4H), 2.41(m, 2H), 2.30 (m, 1H), 1.65 (m, 1H), 1.53 (m, 3H), 1.07-1.06 (m, 5H).

Example 18(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxy-2,3-dimethylphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-208 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=744.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 8.08 (d, 1H),7.86-7.85 (m, 1H), 7.83-7.81 (m, 1H), 7.79 (d, 1H), 7.75 (s, 1H),7.68-7.67 (m, 1H), 7.07-7.05 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 4.19-4.09 (m, 2H), 3.89 (s, 3H), 3.35-3.30 (m, 1H), 3.22 (m, 4H),2.71-2.69 (m, 2H), 2.39-2.36 (m, 7H), 2.19-2.15 (m, 1H), 2.09 (s, 3H),1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 0.98 (t, 3H).

Example 19(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.61, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

The compound was prepared in analogy to route B of example 1, usinghowever oxetane-3-carbaldehyde.

Example 20

N-[(3S)-1-(benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-1 of Table A)

ESI-MS [M+H⁺]=686.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.06-8.04 (m,2H), 7.98-7.96 (m, 1H), 7.87 (d, 1H), 7.83-7.82 (m, 1H), 7.80-7.76 (m,2H), 7.66-7.63 (m, 3H), 7.09-7.07 (m, 1H), 4.52-4.49 (m, 2H), 4.40-4.38(m, 2H), 4.11-4.08 (m, 1H), 4.00-3.95 (m, 1H), 3.78-3.76 (m, 2H), 3.34(m, 1H), 2.61 (m, 2H), 2.50-2.15 (m, 9H), 1.72-1.60 (m, 2H), 1.23-1.12(m, 2H), 0.97 (t, 3H).

Example 21N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90 (d, 1H),7.87 (d, 1H), 7.81-7.80 (m, 1H), 7.75-7.73 (m, 1H), 7.71 (s, 1H), 7.68(m, 1H), 7.05-7.03 (m, 1H), 7.71-7.69 (m, 1H), 6.67 (d, 1H), 4.51-4.49(m, 2H), 4.39-4.37 (m, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H),3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H),2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.36 (m, 2H).

Example 22N-[(3S)-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-5,6-difluoro-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-2757 of Table A)

ESI-MS [M+H⁺]=757.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.12 (m, 1H), 7.87 (d, 1H),7.67-7.62 (m, 3H), 7.38-7.34 (m, 1H), 7.01-6.99 (m, 1H), 6.70-6.67 (m,2H), 4.52-4.49 (m, 2H), 4.42-4.38 (m, 2H), 4.22-4.13 (m, 2H), 3.85 (s,3H), 3.85-3.81 (m, 2H), 3.47 (s, 3H), 3.34 (m, 1H), 2.64-2.60 (m, 2H),2.49-2.22 (m, 9H), 1.64-1.62 (m, 2H), 1.17-1.12 (m, 2H), 1.12 (t, 3H).

Example 23N-[(3R)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(R-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-13 of Table A)

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.97-7.94 (m,3H), 7.87 (m, 1H), 7.82-7.81 (m, 1H), 7.79 (s, 1H), 7.61 (m, 1H),7.17-7.14 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 4.11-4.06 (m, 1H), 4.01-3.98 (m, 1H), 3.84 (s, 3H), 3.17 (s, 3H),2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.67 (m, 4H),1.41-1.33 (m, 2H), 1.26 (m, 2H), 0.98 (t, 3H).

Example 24N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-13 of Table A)

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.97-7.94 (m,3H), 7.86 (m, 1H), 7.82-7.81 (m, 1H), 7.73 (s, 1H), 7.61 (m, 1H),7.15-7.14 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 4.11-4.06 (m, 1H), 4.02-3.98 (m, 1H), 3.81 (s, 3H), 3.17 (s, 3H),2.73-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.67 (m, 4H),1.41-1.33 (m, 2H), 1.23 (m, 2H), 0.98 (t, 3H).

Example 25N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.19, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row B-4 of Table B)

ESI-MS [M+H⁺]=717.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.41-8.40 (d, 1H), 8.16-8.15 (d,1H), 8.14-8.13 (m, 1H), 7.94-7.92 (m, 2H), 7.85-7.83 (m, 1H), 7.73 (s,1H), 7.66-7.64 (m, 1H), 7.62 (d, 1H), 7.08-7.06 (m, 1H), 4.51-4.49 (m,2H), 4.39-4.37 (m, 2H), 4.10-4.02 (m, 2H), 3.91 (s, 3H), 3.34-3.29 (m,1H), 3.15 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.20-2.15 (m, 1H),1.71-1.67 (m, 4H), 1.42-1.36 (m, 2H), 1.02 (t, 3H).

Example 26N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-59 of Table A)

ESI-MS [M+H⁺]=734.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.13 (m, 1H), 8.02-7.99 (m,1H), 7.90-7.83 (m, 3H), 7.70 (s, 1H), 7.66 (d, 1H), 7.18-7.15 (m, 1H),7.08-7.06 (m, 1H), 6.99-6.96 (m, 1H), 4.51-4.48 (m, 2H), 4.39-4.37 (m,2H), 4.18-4.10 (m, 2H), 3.47 (s, 3H), 3.34-3.29 (m, 1H), 3.18 (m, 4H),2.70-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.14 (m, 1H), 1.71-1.65 (m, 4H),1.40-1.34 (m, 2H), 1.06 (t, 3H).

Example 27N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=731.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90-7.87 (m,2H), 7.81-7.80 (m, 1H), 7.73-7.72 (m, 1H), 7.68-7.67 (m, 2H), 7.05-7.03(m, 1H), 6.70-6.68 (m, 1H), 6.67 (d, 1H), 4.51-4.49 (m, 2H), 4.39-4.37(m, 2H), 3.86 (s, 3H), 3.83 (m, 2H), 3.72 (s, 3H), 3.48 (s, 3H),3.32-3.27 (m, 1H), 2.70-2.69 (m, 2H), 2.57-2.52 (m, 2H), 1.65-1.61 (m,2H), 1.56-1.50 (m, 4H), 1.20-1.10 (m, 3H), 1.01-0.88 (m, 3H).

Example 28N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-11 of Table A)

ESI-MS [M+H⁺]=704.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 8.12-8.08 (m,2H), 8.04-8.02 (m, 1H), 7.91-7.90 (d, 1H), 7.84-7.82 (m, 1H), 7.75 (s,1H), 7.61 (d, 1H), 7.51-7.47 (m, 2H), 7.11-7.09 (m, 1H), 4.51-4.49 (m,2H), 4.39-4.37 (m, 2H), 4.12-4.01 (m, 2H), 3.35-3.28 (m, 1H), 3.14 (m,4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.66 (m,4H), 1.41-1.35 (m, 2H), 1.01 (t, 3H).

Example 29N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.22, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row B-4 of Table B)

ESI-MS [M+H⁺]=703.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.45 (m, 1H), 8.21-8.19 (d, 1H),8.15-8.14 (m, 1H), 7.93-7.90 (m, 2H), 7.83-7.82 (m, 1H), 7.77 (s, 1H),7.68-7.66 (m, 1H), 7.65 (d, 1H), 7.10-7.08 (m, 1H), 4.51-4.49 (m, 2H),4.39-4.37 (m, 2H), 3.92 (s, 3H), 3.54 (s, 3H), 3.34-3.29 (m, 1H), 3.19(m, 4H), 2.71-2.69 (m, 2H), 2.39-2.36 (m, 4H), 2.20-2.16 (m, 1H),1.71-1.68 (m, 4H), 1.42-1.38 (m, 2H).

Example 30N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-59 of Table A)

ESI-MS [M+H⁺]=720.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 8.05-8.02 (m,1H), 7.89-7.87 (m, 2H), 7.83-7.81 (m, 1H), 7.73 (s, 1H), 7.68 (m, 1H),7.19-7.17 (m, 1H), 7.10-7.08 (m, 1H), 7.00-6.97 (m, 1H), 4.51-4.49 (m,2H), 4.39-4.37 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 3.34-3.29 (m, 1H),3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.16 (m, 1H), 1.71-1.65(m, 4H), 1.39-1.36 (m, 2H).

Example 31N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.5, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.14 (m, 1H), 7.90-7.87 (m,2H), 7.81-7.80 (m, 1H), 7.74-7.72 (m, 2H), 7.69-7.68 (m, 1H), 7.06-7.04(m, 1H), 6.70-6.67 (m, 2H), 4.53-4.50 (m, 2H), 4.40-4.38 (m, 2H), 3.86(s, 3H), 3.83-3.81 (m, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.34 (m, 1H),2.63-2.59 (m, 2H), 2.45 (m, 4H), 2.35-2.31 (m, 1H), 2.23 (m, 4H),1.63-1.58 (m, 2H), 1.16 (m, 2H).

Example 32N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.31, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row B-4 of Table B)

ESI-MS [M+H⁺]=746.3.

Example 33N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.13, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=775.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.88-7.86 (m, 2H), 7.80-7.78 (m,1H), 7.68-7.67 (m, 1H), 7.63 (m, 1H), 6.91 (m, 3H), 6.69-6.67 (m, 1H),6.64 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.38 (m, 2H), 3.97-3.92 (m, 1H),3.85 (s, 3H), 3.79-3.74 (m, 1H), 3.70 (s, 3H), 3.45 (s, 3H), 3.34 (m,1H), 3.17 (m, 4H), 2.71 (m, 2H), 2.36 (m, 4H), 2.17 (m, 1H), 1.70 (m,4H), 1.39 (m, 2H), 1.12-1.09 (t, 3H).

Example 34N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-13 of Table A)

ESI-MS [M+H⁺]=702.3.

Example 35N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.13, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-59 of Table A)

ESI-MS [M+H⁺]=763.3.

Example 36N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-13 of Table A)

ESI-MS [M+H⁺]=701.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.01-7.99 (m,2H), 7.95-7.94 (m, 1H), 7.86-7.85 (m, 1H), 7.81-7.79 (m, 1H), 7.72 (s,1H), 7.63-7.62 (m, 1H), 7.18-7.15 (m, 2H), 7.10-7.08 (m, 1H), 4.51-4.49(m, 2H), 4.39-4.37 (m, 2H), 3.85 (m, 5H), 3.48 (s, 3H), 3.35-3.26 (m,1H), 2.70-2.69 (m, 2H), 2.57 (m, 2H), 1.66-1.53 (m, 6H), 1.19-1.12 (m,3H), 1.03-0.92 (m, 3H).

Example 37N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-59 of Table A)

ESI-MS [M+H⁺]=719.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 8.04-8.02 (m,1H), 7.90-7.88 (m, 1H), 7.87-7.86 (m, 1H), 7.83-7.81 (m, 1H), 7.69 (s,1H), 7.68-7.67 (m, 1H), 7.19-7.16 (m, 1H), 7.10-7.08 (m, 1H), 6.99-6.96(m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.82-3.80 (m, 2H), 3.71(s, 3H), 3.50 (s, 3H), 3.31-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.52 (m,2H), 1.65-1.61 (m, 2H), 1.56-1.50 (m, 4H), 1.18-1.10 (m, 3H), 1.00-0.89(m, 3H).

Example 38N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-5-[1-(oxetan-3-yl)-4-piperidyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 7 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=758.3.

Example 39N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.24, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row B-4 of Table B)

ESI-MS [M+H⁺]=702.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.45-8.44 (m, 1H), 8.20-8.19 (m,1H), 8.15-8.14 (m, 1H), 7.92-7.90 (m, 2H), 7.83-7.81 (m, 1H), 7.73 (s,1H), 7.68-7.66 (m, 1H), 7.65-7.64 (m, 1H), 7.10-7.08 (m, 1H), 4.51-4.49(m, 2H), 4.39-4.37 (m, 2H), 3.92 (s, 3H), 3.83-3.81 (m, 2H), 3.55 (s,3H), 3.35-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.56 (m, 2H), 1.66-1.62 (m,2H), 1.60-1.54 (m, 4H), 1.19-1.12 (m, 3H), 1.03-0.92 (m, 3H).

Example 40N-[(3S)-5-cyano-1-(4-fluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-11 of Table A)

ESI-MS [M+H⁺]=689.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.12 (m, 3H), 8.03-8.00 (m,1H), 7.90-7.88 (m, 1H), 7.82-7.81 (m, 1H), 7.75 (s, 1H), 7.64 (m, 1H),7.53-7.49 (m, 2H), 7.13-7.11 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m,2H), 3.81 (m, 2H), 3.52 (s, 3H), 3.35-3.27 (m, 1H), 2.70-2.68 (m, 2H),2.55 (m, 2H), 1.66-1.62 (m, 2H), 1.59-1.53 (m, 4H), 1.19-1.11 (m, 3H),1.02-0.91 (m, 3H).

Example 41N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-270 of Table A)

ESI-MS [M+H⁺]=750.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 7.88-7.86 (m,1H), 7.86-7.84 (m, 1H), 7.82-7.80 (m, 1H), 7.76-7.74 (m, 2H), 7.68 (m,1H), 7.09-7.07 (m, 1H), 6.92-6.91 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37(m, 2H), 3.95 (s, 3H), 3.71 (s, 3H), 3.55 (s, 3H), 3.35-3.29 (m, 1H),3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.14 (m, 1H),1.71-1.66 (m, 4H), 1.41-1.36 (m, 2H).

Example 42N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷correspond to row A-270 of Table A)

ESI-MS [M+H⁺]=749.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 7.88-7.87 (m,1H), 7.84-7.80 (m, 2H), 7.75-7.73 (m, 1H), 7.70 (s, 1H), 7.68-7.67 (m,1H), 7.09-7.07 (m, 1H), 6.92-6.90 (m, 1H), 4.51-4.49 (m, 2H), 4.41-4.37(m, 2H), 3.95 (s, 3H), 3.85-3.80 (m, 2H), 3.72 (s, 3H), 3.54 (s, 3H),3.33-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.56 (m, 2H), 1.65-1.61 (m, 2H),1.57-1.51 (m, 4H), 1.20-1.10 (m, 3H), 0.98-0.89 (m, 3H).

Example 43N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-14 of Table A)

ESI-MS: [M+H⁺]=697.25;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.22 (d, 2H), 8.18 (dd, 1H), 8.05 (d,1H), 7.80 (d, 2H), 7.67 (dd, 1H), 7.53-7.54 (m, 1H), 7.33 (dd, 1H), 6.93(m sym., 1H), 6.55 (s, 1H), 4.65 (t, 2H), 4.60 (t, 2H), 4.07 (s, 3H),3.44 (qd, 1H), 3.15-3.22 (m, 2H), 3.12 (br. s., 2H), 2.80 (d, 2H), 2.47(br. s., 4H), 2.30 (br. s., 1H), 1.73-1.85 (m, 4H).

Example 44N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-isopropoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.73, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS: [M+H⁺]=760.30.

Example 45N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-12 of Table A)

ESI-MS: [M+H⁺]=686.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.15 (dd, 1H), 7.99-8.02 (m, 3H), 7.61(dd, 1H), 7.55 (d, 1H), 7.32 (d, 2H), 6.87 (dd, 1H), 6.59 (br. s., 1H),4.63-4.66 (m, 2H), 4.60 (br. s, 2H), 4.05 (s, 3H), 3.44 (m sym., 1H),3.24 (br. s., 2H), 3.20 (br. s., 2H), 2.81 (d, 2H), 2.48 (br. s., 3H),2.42 (s, 3H), 2.31 (br. s., 1H), 1.76-1.83 (br. m., 4H).

Example 46N-[(3S)-5-cyano-1-(2-methoxy-4-methyl-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-60 of Table A)

ESI-MS: [M+H⁺]=716.30;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.14 (ddd, 1H), 8.09 (dd, 1H), 8.02(d, 1H), 7.62 (t, 2H), 7.25-7.29 (m, incl. CHCl₃), 7.22 (d, 1H), 7.22(d, 1H), 6.85 (dd, 1H), 6.74 (s, 1H), 6.64 (br. m, 1H), 4.65 (t, 2H),4.59 (br. s, 2H), 4.08-4.10 (m, 3H), 3.52-3.54 (m, 3H), 3.44 (br. m,1H), 3.23 (br. s., 4H), 2.80 (d, 2H), 2.47 (br. s., 3H), 2.39-2.41 (m,3H), 2.30 (br. s., 1H), 1.74-1.82 (m, 4H).

Example 47N-[(3S)-5-cyano-1-(4-cyano-2-fluoro-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-30 of Table A)

ESI-MS: [M+H⁺]=715.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.29 (t, 1H), 8.18 (dd, 1H), 8.10 (d,1H), 7.68 (dd, 1H), 7.60 (dd, 1H), 7.56 (s, 1H), 7.46 (dd, 1H), 7.33(dd, 1H), 6.93 (m, 1H), 6.52 (br. s., 1H), 4.64 (t, 2H), 4.59 (br. m,2H), 4.07 (s, 3H), 3.44 (quint, 1H), 3.19 (br. s, 2H), 3.10 (br. s.,2H), 2.80 (d, 2H), 2.46 (br. s., 4H), 2.30 (br. s., 1H), 1.74-1.82 (m,4H).

Example 48N-[(3S)-5-cyano-1-(2,4-difluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-27 of Table A)

ESI-MS: [M+H⁺]=708.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.16-8.21 [m, 2H, incl. 8.17 (d, 1H)],8.11 (d, 1H), 7.67 (dd, 1H), 7.56 (d, 1H), 7.30 (d, 1H), 7.04 (td, 1H),6.89-6.93 (m, 2H), 6.57 (br. s., 1H), 4.63-4.66 (m, 2H), 4.58-4.62 (m,2H), 4.07 (s, 3H), 3.44 (br. s., 1H), 3.23 (br. s., 2H), 3.14 (br. s.,2H), 2.80 (d, 2H), 2.46 (br. s., 3H), 2.29 (br. s., 1H), 1.73-1.81 (m,4H).

Example 49(S)—N-(5-cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspondto row A-4 of Table A)

ESI-MS [M+H⁺]=701.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.14 (m, 1H), 8.00-7.98 (m,1H), 7.90-7.88 (m, 1H), 7.83-7.81 (m, 1H), 7.77-7.75 (m, 1H), 7.72-7.69(m, 3H), 7.23-7.21 (m, 1H), 7.16-7.13 (m, 1H), 7.06-7.04 (m, 1H),4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.84-3.82 (m, 2H), 3.70 (s, 3H),3.50 (s, 3H), 3.31-3.26 (m, 1H), 2.70-2.68 (m, 2H), 2.57-2.52 (m, 2H),1.65-1.50 (m, 6H), 1.18-1.11 (m, 3H), 1.04-0.88 (m, 3H).

Example 50(S)—N-(5-cyano-3-(2-methoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspondto row A-1 of Table A)

ESI-MS [M+H⁺]=671.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.10-8.08 (m,2H), 7.99-7.98 (m, 1H), 7.88-7.86 (m, 1H), 7.82-7.78 (m, 2H), 7.75 (s,1H), 7.68-7.66 (m, 2H), 7.64 (d, 1H), 7.11-7.09 (m, 1H), 4.51-4.49 (m,2H), 4.39 (m, 2H), 3.86-3.84 (m, 2H), 3.43 (s, 3H), 3.32-3.27 (m, 1H),2.70 (m, 2H), 2.59-2.55 (m, 2H), 1.64-1.54 (m, 6H), 1.17 (m, 3H),1.01-0.92 (m, 3H).

Example 51(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 20 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=760.4;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.88-7.86 (m,2H), 7.83-7.81 (m, 1H), 7.75-7.73 (m, 1H), 7.69-7.68 (m, 2H), 7.04-7.01(m, 1H), 6.70-6.68 (m, 1H), 6.66 (m, 1H), 4.37-4.34 (m, 2H), 4.19-4.11(m, 2H), 4.09-4.08 (m 2H), 3.85 (s, 3H), 3.44 (s, 3H), 3.20 (m, 3H),3.13-3.12 (m, 2H), 2.55-2.53 (m, 2H), 2.35 (m, 3H), 1.17-1.13 (m, 1H),1.99-1.95 (m, 2H), 1.67-1.66 (m, 2H), 1.39-1.35 (m, 2H), 1.23 (s, 3H),1.07-1.04 (m, 3H).

Example 52(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide,2 trifluoroacetic acid

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 20 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=746.2.

Example 53N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(2-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide,2 trifluoroacetic acid

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 21 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=746.4.

Example 54(S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.16, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=761.2;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.89 (d, 1H), 7.84 (d, 1H), 7.77(dd, 1H), 7.65 (d, 1H), 7.61 (s, 1H), 7.03 (d, 1H), 6.91 (m, 2H), 6.68(dd, 1H), 6.66 (d, 1H), 4.50 (t, 2H), 4.38 (t, 2H), 3.85 (s, 3H), 3.73(s, 3H), 3.55 (s, 3H), 3.50 (s, 3H), 3.31 (m, overlapped with H₂O), 3.18(m, 4H), 2.70 (m, 2H), 2.37 (m, 4H), 2.15 (m, 1H), 1.68 (m, 4H), 1.38(m, 2H).

Example 55(S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.18, wherein R^(8a), R^(8b),R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) andR^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspondto row A-61 of Table A)

ESI-MS [M+H⁺]=760.2;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.89 (d, 1H), 7.86 (d, 1H), 7.76(dd, 1H), 7.64 (d, 1H), 7.58 (s, 1H), 7.13 (d, 1H), 6.94 (d, 1H), 6.89(dd, 1H), 6.66 (dd, 1H), 6.65 (m, 1H), 4.50 (t, 2H), 4.38 (m, 2H), 3.83(s, 3H), 3.82 (m, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.49 (s, 3H), 3.29(m, 2H), 2.69 (m, 2H), 2.53 (m, overlapped with DMSO) 1.63 (m, 2H), 1.53(m, 4H), 1.09-0.89 (m, 3H).

III. Determination of the Biological Activity III.1 In Vitro Experiments

1. Vasopressin V1b Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 5 mM in 100%DMSO and further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M. These serial DMSOpredilutions were diluted 1:10 with assay buffer. The substanceconcentration was further diluted 1:5 in the assay mixture resulting in2% DMSO in the mixture. All dilutions were performed in a Biomek NXautomation workstation (Beckman)

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) using aPolytron homogenizer at intermediate setting for 2×10 seconds, andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and subsequently taken upin 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen inliquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (26 μg protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer, NET 800) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP (Fluka94836). All determinations were carried out as duplicate determinations.After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Tomtec Mach III) through WathmanGF/B glass fiber filter plates (UniFilter, PerkinElmer 6005177). Theliquid scintillation measurement took place in a Microbeta TriLux 12(Wallac).

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki.

2. Vasopressin V1a Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 5 mM M in DMSO.Further dilution of these DMSO solutions took place as described forV1b.

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized in a High-Pressure-Homogenizer, Polytec 50K at 1500 PSI(Heinemann, Germany) and subsequently taken up in 50 mM Tris-HCl, pH7.4, homogenized and stored in aliquots frozen in liquid nitrogen at−190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (40 g protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, PerkinElmer NEX 128) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP (Fluka94836). Duplicate determinations were carried out.

After incubation (60 minutes at room temperature), the samples wereprocessed as described for V1b.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki.

3. Oxytocin Receptor Binding Assay

Substances:

The substances were dissolved in a concentration of 5 mM in DMSO anddiluted further as described for V1b.

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g at room temperature for 5minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzedcells were then centrifuged at 750×g at 4° C. for 20 minutes, theresidue was taken up in incubation buffer, and aliquots of 10⁷ cells/mlwere prepared. The aliquots were frozen at −80° C. until used.

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), ghosts corresponding to 5×10⁴ cells(HEK-293 cells expressing transiently human OT receptors) were incubatedwith 3H-oxytocin (PerkinElmer NET858) in incubation buffer (50 mM Tris,10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally withincreasing concentrations of test substance (displacement experiment).The nonspecific binding was determined with 1 M A-797879 (AbbVie,Ludwigshafen, Germany). Duplicate determinations were carried out.

After incubation (60 minutes at room temperature), the samples wereprocessed as described for V1b.

Binding Assay:

Analysis:

The binding parameters were calculated by nonlinear regression analysis(SAS) in analogy to the LIGAND program of Munson and Rodbard (AnalyticalBiochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinanthOT receptors is 7.6 nM and was used to determine the Ki.

4. Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance are preincubated together with liver microsomesfrom different species (from rat, human or other species) (0.25 mg ofmicrosomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 inmicrotiter plates at 37° C. for 5 min. The reaction is started by addingNADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots areremoved, and the reaction is immediately stopped and cooled with thesame volume of acetonitrile. The samples are frozen until analyzed. Theremaining concentration of undegraded test substance is determined byMSMS. The half-life (T½) is determined from the gradient of the signalof test substance/unit time plot, it being possible to calculate thehalf-life of the test substance, assuming first order kinetics, from thedecrease in the concentration of the compound with time. The microsomalclearance (mCl) is calculated from mCl=ln 2/T½/(content of microsomalprotein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, TheSociety for Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol27. N 11, 1350-1359).5. Methods for In Vitro Determination of the Cytochrome P450 (CYP)InhibitionLuminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the testsubstances to be investigated (0-20 M), the CYP-specific substrates, in0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. TheCyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 isluciferin BE. The reaction is started by adding NADPH. After incubationat RT for 30 min, the luciferin detection reagent is added, and theresulting luminescence signal is measured (modified from reference:Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-Dependent Inhibition

The assay consists of 2 parts. Firstly, the test substance ispreincubated with the liver microsomes (with NADPH=preincubation, thenaddition of the substrate; in the second part the substrate and the testsubstance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 0-10 M (or 50 M) test substance in 50 mM potassium phosphate bufferfor 5 min. The reaction is started with NADPH. After 30 min 4 Mmidazolam (final concentration) are added, and incubation is continuedfor 10 min. 75 μl of the reaction solution are removed after 10 min, andstopped with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 4 μm midazolam (final concentration) and 0-10 μM (or 50 μM) testsubstance in 50 mM potassium phosphate buffer for 5 min. The reaction isstarted with NADPH. 75 μl of the reaction solution are removed after 10min and stopped with 150 μl of acetonitrile solution. The samples arefrozen until the MSMS analysis (modified from references: Obdach,Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1,336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6,647-660, 2004).

6. Method for Determining the Solubility in Water (in mg/ml)

The solubility in water of the compounds of the invention can bedetermined for example by the so-called shake flask method (as specifiedin ASTM International: E 1148-02, Standard test methods for measurementof aqueous solubility, Book of Standards Volume 11.05.). This entails anexcess of the solid compound being put into a buffer solution with aparticular pH (for example phosphate buffer of pH 7.4), and theresulting mixture being shaken or stirred until equilibrium has been setup (typically 24 or 48 hours, sometimes even up to 7 days). Theundissolved solid is then removed by filtration or centrifugation, andthe concentration of the dissolved compound is determined by UVspectroscopy or high pressure liquid chromatography (HPLC) by means ofan appropriate calibration plot.

7. Results

The results of the receptor binding investigations are expressed asreceptor binding constants [K_(i)(V1b)] or selectivities[K_(i)(V1a)/K_(i)(V1b)]. The results of the investigation of themetabolic stability are indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1breceptor in these assays (maximally 100 nM, or maximally 10 nM,frequently<1 nM). The compounds also show high selectivities vis-à-visthe V1a receptor and a good metabolic stability, measured as microsomalclearance.

The results are listed in table C. The numbers of the compounds refer tothe synthesis examples.

TABLE C Example K_(i)(h-V1b)* [nM] K_(i)(h-V1a)/K_(i)(h-V1b) 1 +++ +++ 2++ ++ 3 ++ 4 + 5 ++ 6 ++ +++ 7 +++ 7A +++ +++ 8 ++ +++ 9 ++ +++ 10 ++++++ 11 +++ +++ 12 + ++ 13 + +++ 14 ++ ++ 15 ++ +++ 16 + 17 + ++ 18 + +19 + +++ 21 + +++ 24 + +++ 25 ++ +++ 26 ++ +++ 27 +++ +++ 28 + +++ 29++ + 30 ++ +++ 31 + +++ 32 + +++ 33 ++ +++ 34 + ++ 35 ++ +++ 36 ++ +++37 +++ +++ 38 + +++ 39 +++ 40 ++ + 43 + + 44 ++ +++ 46 + +++ 47 + ++ 49++ +++ 50 + ++ 51 ++ +++ 52 ++ +++ 53 ++ ++ 54 +++ ++ 55 +++ + *h =humanKey:

K_(i)(h-V1b) K_(i)(h-V1a)/K_(i)(h-V1b) + >10-100 nM  10-<25 ++    1-10nM 25-75 +++     <1 nM >75III.2 Determination of Preclinical In Vivo Efficacy1. MethodsAnimals

Male NMRI mice (Janvier, Le Genest-St-Isle, France) were used forstress-induced Adrenocorticotropic hormone (ACTH) release. Adult maleWistar rats (175-220 g body weight upon arrival) were obtained fromHarlan Inc. (Indianapolis, Ind.). For the forced swim test, male SpragueDawley rats (100-120 g body weight upon arrival) were obtained fromJanvier (Le Genest-St-Isle, France). The animals were acclimatized tothe animal facilities for at least one week before the start of theexperimental procedures. Animals were maintained in a controlledenvironment on a 12:12 hour light dark schedule (lights on 06:00 h forrats in Vogel conflict test and 05:30 h for rats in forced swim test).Experimental procedures took place during the illuminated phase of thelight/dark cycle. Food and water were available ad libitum, except forthe Vogel conflict test, where the animals were submitted to a waterdeprivation regimen as described below. The experiments were performedin compliance with the German Animal Protection law (Tierschutzgesetz,Neufassung vom May 25, 1998), the EC directive 86/609 (J of the EC No.L358/1 dated 18 Dec. 1986), Abbott's Institutional Animal Care and UseCommittee and the National Institute of Health Guide for Care and Use ofLaboratory Animals guidelines in facilities fully accredited by theAssociation for the Assessment and Accreditation of Laboratory AnimalCare (AAALAC).

Tested Compound

The compound of example 21 was used in the below-described tests.

1.1 Stress-Induced ACTH Release

Arginine vasopressin (AVP), a key regulator of the HPA axis, is a cyclicpeptide that is synthesized in the hypothalamus. Vasopressin is releasedfrom the median eminence into the pituitary portal circulation where itactivates HPA activity by stimulation of the pituitary V1B receptor.This results in an increased adrenocorticotropin (ACTH) release which inturn enhances the release of corticosterone in rodents and cortisol inhumans from the adrenal glands. Dysregulation of the HPA axis is commonin major depression including elevated AVP, increased responsiveness toAVP, as well as either increased or decreased overall HPA axis activityor responsiveness. Therefore, antagonism of the V1B receptor is apotential target for therapeutic intervention.

Animals were subjected to single housing in Type II cages three daysbefore the experiment. At least one day before the experiment they weretransferred from the animal facility into the experimental room wherethey were housed in Scantainers (Type D, Scanbur Ltd., Demark) until thenext day. The compound of example 21 or vehicle were appliedintraperitoneally (i.p.) 1 hour before the animals were transferred intoperforated transparent plastic tubes (diameter 2.5 cm) for a period of15 minutes to expose them to restraint stress. Non-stressed controlanimals were left in their home cage for the same time. Thereafter themice were anaesthetized with isoflurane and blood samples were taken bycardiac puncture. Immediately after blood sampling and still underanesthesia animals were sacrificed by cervical dislocation. Furtherprocessing of the blood samples to generate plasma and the determinationof ACTH and corticosterone was performed.

The blood was collected in 1.3 mL blood sampling vials containingpotassium EDTA (Sarstedt, Nümbrecht, Germany) and 10 L aprotininsolution (saline solution, 3-7 TIU [trypsin inhibitor units]/mg protein;Sigma-Aldrich, Germany). The samples were centrifuged at 2500×g for 20minutes to obtain the plasma. ACTH concentrations were measured by anELISA (enzyme-linked immuno sorbent assay) for ACTH (IBL Hamburg,Germany). Prior to the ELISA, samples were diluted 2.5-fold withcalibrator A (Zero Calibrator; IBL Hamburg, Germany) provided with theELISA kit.

1.2 Vogel Conflict Test

The Vogel conflict test is a well-validated animal model to detectcompounds with anxiolytic properties. In this model, water-deprivedanimals face the conflict of receiving a mild shock when they drinkwater from a metal spigot. Anxiolytic compounds tested in this modelinduce a significant increase in the number of punished responses. Ratswere water-deprived for 48 h before testing. After 24 h of waterdeprivation, rats were habituated to the testing chambers (CoulbournInstruments, Whitehall, Pa.) and allowed to drink for 15 min (trainingsession), with an additional 15 min drinking in their home cages. Waterdeprivation then continued for another 24 h. On the test day, rats wereplaced in the chambers with access to the water spigot. Every 20 licks,they received one shock (0.5 mA, 1 s duration) delivered through thedrinking tube. The number of punished responses was automaticallyrecorded for each rat during 5 min of testing. The compound of example21 was tested at the doses of 3, 10 and 30 mg/kg i.p. It wasadministered once on the testing day, 30 minutes before the test.

1.3 Forced Swim Test

The forced swim test has been developed to evaluate antidepressantcompounds. Its usefulness is based on the observation that efficacy isseen with many different classes of antidepressant compounds as well aselectroconvulsive shock. Forced swim tests are often used for thescreening of new antidepressant drugs, but have also been used toinvestigate depressive-like behavior induced by drugs.

The forced swim test consisted of a pre-test and a test swim. Rats wereindividually placed for 15 min into cylinders (height: 40 cm, diameter:21.5 cm) containing 30 cm of water at 25° C. Following this pre-testswim, animals were removed and allowed to dry in a heated enclosurebefore returning to their home cages. Twenty-four hours later, rats weresubmitted to the test swim, in which they were placed again in thecylinder for 5 min. Test swims were recorded on videotape andsubsequently used for analysis. Latency to immobility was taken as ameasure of efficacy. The compound of example 21 was tested in the forcedswim test at the doses of 3, 10 and 30 mg/kg i.p. The compound wasadministered 24, 4 and 0.5 hours before testing, with the firstinjection given 15 minutes after the pre-swim session on Day 1.

2. Results

FIG. 1 shows ACTH release dependent on the administered dose rate of thecompound of example 21.

FIG. 2 shows punishment responses dependent on the administered doserate of the compound of example 21.

FIG. 3 shows latency to immobility dependent on the administered doserate of the compound of example 21.

In the figures, the asterisk (*) indicates a statistically significantdifference compared to the control.

2.1 Stress-Induced ACTH Release

As FIG. 1 shows, injection of the compound of example 21 significantlyblocked stress-induced ACTH release. Example 21 significantly blockedthe stress response at 10 and 30 mg/kg.

2.2 Vogel Conflict Test

As FIG. 2 shows, application of the compound of example 21 resulted indose dependent anxiolytic-like efficacy in Vogel conflict. The compoundof example 21 showed significant effect at 10 and 30 mg/kg.

2.3 Forced Swim Test

As FIG. 3 shows, application of the compound of example 21 increased thelatency to immobility in the forced swim test. The compound of example21 showed a significant antidepressant-like effect at 10 mg/kg.

The invention claimed is:
 1. A compound of formula I

wherein X¹ and X² are N or CH, with the proviso that X¹ and X² are notsimultaneously N; X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene orCO; X⁴ is N or CH; X⁵ is C—R¹ or N; R¹ and R², independently of eachother, are selected from the group consisting of hydrogen, halogen,cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl,C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; R³ is selected from the groupconsisting of hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinatedC₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, fluorinated C₁-C₃-alkoxyand hydroxyl; R⁴ is C₁-C₃-alkoxy; R⁵ is hydrogen or C₁-C₃-alkoxy; R⁶ iscyano or halogen; R⁷ is selected from the group consisting of hydrogen,halogen and cyano; R⁸ and R⁹, independently of each other andindependently of each occurrence, are selected from the group consistingof halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with theproviso that R⁸ and R⁹ are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxyif they are bound to a carbon atom in α-position to a nitrogen ringatom; or two non-geminal radicals R⁸ form together a group (CH₂)_(n)—,where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group maybe replaced a methyl group; or two non-geminal radicals R⁹ form togethera group —(CH₂)_(n)—, where n is 1, 2, 3 or 4, where 1 or 2 hydrogenatoms in this group may be replaced a methyl group; each R¹⁰ isindependently selected from the group consisting of halogen, C₁-C₄-alkyland C₁-C₄-haloalkyl; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; and cis 0, 1, 2, 3 or 4; or an N-oxide, stereoisomer or pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, where R¹, R² andR³, independently of each other, are selected from the group consistingof hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy.
 3. Thecompound of claim 2, where R² is selected from the group consisting ofhydrogen, cyano, methoxy and fluorine.
 4. The compound of claim 2, whereR² is methyl.
 5. The compound of claim 1, where R⁴ is methoxy or ethoxy.6. The compound of claim 1, where R⁴ is isopropoxy.
 7. The compound ofclaim 1, where R⁵ is hydrogen or methoxy.
 8. The compound of claim 1,where R⁶ is selected from the group consisting of cyano, fluorine andchlorine.
 9. The compound of claim 1, where R⁷ is hydrogen or fluorine.10. The compound of claim 1, where each R⁸ is independently halogen orC₁-C₄-alkyl, with the proviso that R⁸ is not halogen if it is bound to acarbon atom in α-position to a nitrogen ring atom, or two non-geminalradicals R⁸ form together a group —CH₂—.
 11. The compound of claim 10,where two non-geminal radicals R⁸ form together a group —CH₂—.
 12. Thecompound of claim 11, where the two non-geminal radicals R⁸ formingtogether a group —CH₂— are bound in 2- and 5-position, relative to the1-position of X¹.
 13. The compound of claim 1, where each R⁹ isindependently halogen or C₁-C₄-alkyl, with the proviso that R⁹ is nothalogen if it is bound to a carbon atom in α-position to a nitrogen ringatom, or two non-geminal radicals R⁹ form together a group —CH₂—. 14.The compound of claim 13, where two non-geminal radicals R⁹ formtogether a group —CH₂—.
 15. The compound of claim 14, where the twonon-geminal radicals R⁹ forming together a group —CH₂— are bound in 2-and 5-position, relative to the 1-position of X².
 16. The compound ofclaim 1, where each R¹⁰ is independently halogen or C₁-C₄-alkyl.
 17. Thecompound of claim 1, where X³ is a bond or CH₂.
 18. The compound ofclaim 17, where X³ is a bond.
 19. The compound of claim 1, where X⁴ isN.
 20. The compound of claim 1, where X⁴ is CH.
 21. The compound ofclaim 1, where X⁵ is C—R¹.
 22. The compound of claim 1, where X⁵ is N.23. The compound of claim 1, where a is 0, 1 or
 2. 24. The compound ofclaim 1, where b is 0, 1 or
 2. 25. The compound of claim 1, where c is0, 1 or
 2. 26. The compound of claim 1, selected from the groupconsisting of:(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperadine-1-carboxamide;N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide;(S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;(S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxamide;(S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxy-2,3-dimethylphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)piperazine-1-carboxamide;N-[(3S)-1-(benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-]-yl)piperadine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-5,6-difluoro-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide;N-[(3R)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-5-[1-(oxetan-3-yl)-4-piperidyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide;N-[(3S)-5-cyano-1-(4-fluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide;N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-isopropoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2-methoxy-4-methyl-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(4-cyano-2-fluoro-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;N-[(3S)-5-cyano-1-(2,4-difluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide;(S)—N-(5-cyano-3-(2-methoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(2-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;(S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;and(S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide;or an N-oxide, stereoisomer, racemate or pharmaceutically acceptablesalt thereof.
 27. A pharmaceutical composition comprising at least onecompound of the formula I of claim 1 or an N-oxide, a stereoisomer orpharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier.
 28. A method for the treatment of adisease selected from the group consisting of hypertension, pulmonaryhypertension, heart failure, myocardial infarction, coronary spasm,anxiety disorders, stress-dependent anxiety disorders, and depressivedisorders selected from major depression, seasonal depression,treatment-resistant depression, dysthymic disorders and childhood onsetmood disorders, the method comprising administering an effective amountof at least one compound of the formula I of claim 1, or an N-oxide,stereoisomer or pharmaceutically acceptable salt thereof, to a patientin need thereof.